JP7787635B2 - Compositions and methods for treating CNS disorders - Google Patents

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62/867,618, filed June 27, 2019, the entire contents of which are incorporated herein by reference.

Brain excitability is defined as the level of an animal's excitement, a continuum ranging from coma to seizures, and is regulated by various neurotransmitters. Generally, neurotransmitters are responsible for regulating the conduction of ions across the neuronal membrane. At rest, neuronal membranes have a potential (or membrane voltage) of approximately -70 mV, with the interior of the cell negative relative to the exterior. This potential (voltage) is the result of the balance of ions (K ⁺ , Na ⁺ , Cl ^- , organic anions) across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of a neuronal action potential. Upon release into the synaptic cleft, excitatory chemical transmitters such as acetylcholine cause membrane depolarization (a change in potential occurs between -70 mV and -50 mV). This effect is mediated by postsynaptic nicotinic receptors, which, stimulated by acetylcholine, increase membrane permeability to Na ⁺ ions. The decrease in membrane potential stimulates neuronal excitability in the form of a postsynaptic action potential.

In the case of the GABA receptor complex (GRC), its influence on brain excitability is mediated by the neurotransmitter gamma-aminobutyric acid (GABA). GABA profoundly influences overall brain excitability, as up to 40% of neurons in the brain utilize GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by modulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition sites on the GRC, facilitating chloride ions flowing down the GRC's electrochemical gradient into the cell. Intracellular increases in the levels of this anion cause hyperpolarization of the transmembrane potential, making the neuron less susceptible to excitatory inputs, i.e., a decrease in neuronal excitability. In other words, the higher the concentration of chloride ions within a neuron, the lower the brain's excitability and arousal levels.

It is well documented that the GRC plays a role in mediating anxiety, seizure activity, and sedation. Accordingly, GABA and drugs that act like GABA or potentiate its effects (e.g., therapeutically useful barbiturates and benzodiazepines (BZs), e.g., Valium®) exert their therapeutically useful effects by interacting with specific regulatory sites on the GRC. Accumulating evidence now indicates that, in addition to binding sites for benzodiazepines and barbiturates, the GRC contains distinct sites for neuroactive steroids. See, e.g., Lan, N. C. et al., Neurochem. Res. (1991) 16:347-356.

Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one, which are metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M.D. et al., Science 232:1004-1007 (1986); Harrison, N.L. et al., J. Pharmacol. Exp. Ther. 241:346-353 (1987)).
There is a need for new and improved compounds that function as modulators of brain excitability and as agents for the prevention and treatment of CNS-related disorders. The compounds, compositions, and methods described herein are directed toward this end.

Lan, N. C. et al. , Neurochem. Res. (1991) 16:347-356 Majewska, M. D. et al. , Science 232:1004-1007 (1986) Harrison, N. L. et al. , J Pharmacol. Exp. Ther. 241:346-353 (1987)

Provided herein, for example, are compounds designed to act as GABA modulators. In some embodiments, such compounds are contemplated to be useful as therapeutic agents for treating CNS-related disorders.

In certain aspects, provided herein are compounds of formula I:
or a pharmaceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

In certain aspects, provided herein are compounds of formula II:
or a pharmaceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

In some embodiments, the compound of Formula II is a compound of Formula IIIa or IIIb:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, provided herein are compounds of formula V:
or a pharmaceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

In certain aspects, provided herein are compounds of formula VIa or VIb:
or a pharmaceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

In certain aspects, provided herein are compounds of formula VII:
or a pharmaceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

In certain aspects, provided herein are compounds of Formula VIII:
or a pharmaceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

In some embodiments, provided herein are compounds of formula IX:
or a pharmaceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

In certain aspects, provided herein are compounds of formula X:
or a pharmaceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

In one aspect, provided herein are pharmaceutically acceptable salts of compounds described herein (e.g., compounds of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X).

In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in the pharmaceutical composition in an effective amount. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

In one aspect, a method of treating a CNS-related disorder in a subject in need thereof comprises administering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and/or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus. In some embodiments, the CNS-related disorder is depression. In some embodiments, the CNS-related disorder is postpartum depression. In some embodiments, the CNS-related disorder is major depressive disorder. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

In some embodiments, the compound is selected from the group consisting of compounds identified in Table 1 herein.

The compounds of the invention described herein, in certain embodiments, function as GABA modulators, e.g., by acting on GABA _A receptors in either a positive or negative manner. Such compounds are expected to have central nervous system (CNS) activity as mediated by their ability to modulate GABA _A receptors as regulators of CNS excitability.

Accordingly, in another aspect, there is provided a method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention. In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

As generally described herein, the present invention provides compounds designed to function, for example, as GABA _A receptor modulators. In certain embodiments, it is contemplated that such compounds are useful as therapeutic agents for treating CNS-related disorders (e.g., disorders described herein, e.g., depression, such as postpartum depression or major depressive disorder).

Definitions Chemical Definitions Definitions of certain functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS Edition, Handbook of Chemistry and Physics, 75th Ed. endpapers, and certain functional groups are generally defined as described herein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in detail in "Organic Chemistry," by Thomas Sorrell, "Organic Chemistry," University Science Books, Sausalito, 1999; Smith and March, "March's Advanced Organic Chemistry," 5th Edition, John Wiley & Sons, Inc. , New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and chiral salt formation and crystallization, or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al. , Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

"Stereoisomers": It should also be understood that compounds that have identical molecular formulas but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers." Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers." Stereoisomers that are not mirror images of each other are referred to as "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are referred to as "enantiomers." When a compound has an asymmetric center, for example, when a compound is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture."

As used herein, an enantiomerically pure compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that a compound contains more than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R position/center/carbon compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may contain, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound may contain, for example, about 90% excipients and about 10% of the enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may contain, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

The term "diastereomerically pure" means that a compound contains greater than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, or greater than 99.9% by weight of a single diastereomer. Methods for determining diastereomeric and enantiomeric purity are well known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomer, for example, high-performance liquid chromatography (HPLC).

The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analog" means one analog or two or more analogs.

When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, "C _1-6 alkyl" is intended to encompass C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C 1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-5 , C _2-4 , C _{2-3 , C 3-6 ,} C _3-5 , C _3-4 , C _4-6 , C _{4-5 ,} and C _5-6 alkyl.

The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present invention.

"Alkyl" refers to the radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("Ci _-20 alkyl"). In some embodiments, an alkyl group has 1 to 12 carbon atoms ("Ci _-12 alkyl"). In some embodiments, an alkyl group has 1 to 10 carbon atoms ("Ci _-10 alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("Ci _-9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("Ci _-8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("Ci _-7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("Ci _-6 alkyl", referred to herein as "lower alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("Ci _-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("Ci _-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C _1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C _{1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C 1} alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C _2-6 alkyl"). Examples of C _1-6 alkyl groups are methyl (C _{1 ), ethyl (C 2 )} , n-propyl (C 3 ), isopropyl (C ₃ ), n-butyl (C ₄ ), tertiary butyl (C ₄ ), sec-butyl (C ₄ ), iso _{-butyl (C 4 ), n-pentyl (C 5 ) ,} 3-pentanyl (C ₅ ), amyl (C ₅ ), neopentyl (C ₅ ), 3-methyl-2-butanyl (C ₅ ), tertiary amyl (C ₅ ), and n-hexyl ₍ C ₆ ). Additional examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ), and the like. Unless otherwise specified, each example of an alkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C _1-10 alkyl (e.g., —CH ₃ ). In certain embodiments, an alkyl group is a substituted C _1-10 alkyl. Common abbreviations for alkyl include Me(-CH ₃ ), Et(-CH ₂ CH ₃ ), iPr(-CH(CH ₃ ) ₂ ), nPr(-CH ₂ CH ₂ CH ₃ ), n-Bu(-CH ₂ CH ₂ CH ₂ CH ₃ ), or i-Bu(-CH ₂ CH(CH ₃ ) ₂ ).

"Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), pentylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), hexylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), and the like. For example, exemplary substituted alkylene groups substituted with one or more alkyl (methyl) groups include substituted methylene (-CH( _CH3 )-, (-C( _CH3 ) _2- ), substituted ethylene ( _-CH ( _CH3 ) _CH2- , _{-CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2- ) , substituted propylene ( -CH} ( _CH3 ) _CH2CH2- , -CH2CH( _CH3 ) _CH2- , _-CH2CH2CH ( _CH3 ) _- , _-C ( _CH3 ) _2CH2CH2- , _{-CH2C ( CH3 ) 2CH2-} , _-CH2CH2C ( _{CH3 ) 2- ) .} -), and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a linear divalent carbon chain. An alkylene group can be substituted or unsubstituted with one or more substituents described herein.

"Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C _2-20 alkenyl"). In certain embodiments, an alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has from 2 to 10 carbon atoms ("C _2-10 alkenyl"). In some embodiments, an alkenyl group has from 2 to 9 carbon atoms ("C _2-9 alkenyl"). In some embodiments, an alkenyl group has from 2 to 8 carbon atoms ("C _2-8 alkenyl"). In some embodiments, an alkenyl group has from 2 to 7 carbon atoms ("C _2-7 alkenyl"). In some embodiments, an alkenyl group has from 2 to 6 carbon atoms ("C _2-6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (" _C2-5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (" _{C2-4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3} alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms (" _C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2 _- butenyl) or terminal (e.g., in 1-butenyl). Examples of _C2-4 alkenyl include ethenyl ( _C2 ), 1-propenyl ( _C3 ), 2-propenyl ( _C3 ), 1-butenyl ( _C4 ), 2-butenyl ( _C4 ), butadienyl ( _C4 ), and the like. Examples of _C2-6 alkenyl groups include the aforementioned _C2-4 alkenyl groups, as well as pentenyl ( _C5 ), pentadienyl ( _C5 ), hexenyl ( _C6 ), and the like. Additional examples of alkenyl include heptenyl ( _C7 ), octenyl ( _C8 ), octatrienyl ( _C8 ), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkenyl"). In certain embodiments, an alkenyl group is unsubstituted _C2-10 alkenyl. In certain embodiments, an alkenyl group is substituted _C2-10 alkenyl.

"Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C _2-20 alkenyl"). In certain embodiments, an alkenyl does not contain any double bonds. In some embodiments, an alkynyl group has from 2 to 10 carbon atoms ("C _2-10 alkynyl"). In some embodiments, an alkynyl group has from 2 to 9 carbon atoms ("C _2-9 alkynyl"). In some embodiments, an alkynyl group has from 2 to 8 carbon atoms ("C _2-8 alkynyl"). In some embodiments, an alkynyl group has from 2 to 7 carbon atoms ("C _2-7 alkynyl"). In some embodiments, an alkynyl group has from 2 to 6 carbon atoms ("C _2-6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (" _C2-5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (" _{C2-4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-3} alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms (" _C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., in 2 _- butynyl) or terminal (e.g., in 1-butynyl). Examples of _C2-4 alkynyl include, without limitation, ethynyl ( _C2 ), 1-propynyl ( _C3 ), 2-propynyl ( _C3 ), 1-butynyl ( _C4 ), 2-butynyl ( _C4 ), and the like. Examples of _C2-6 alkenyl groups include the aforementioned _C2-4 alkynyl groups, as well as pentynyl ( _C5 ), hexynyl ( _C6 ), and the like. Additional examples of alkynyl include heptynyl ( _C7 ), octynyl ( _C8 ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkenyl"). In certain embodiments, an alkynyl group is unsubstituted _C2-10 alkynyl. In certain embodiments, an alkynyl group is substituted _C2-10 alkynyl.

As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, _{2, 3} , or 4 heteroatoms ("heteroCi_io alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2 _{, 3} , or 4 heteroatoms ("heteroCi_g alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, ₃ , or 4 heteroatoms ("heteroCi_g alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCi_7 alkyl"). In some embodiments, a heteroalkyl group is a group having 1 _to 6 carbon atoms and 1, ₂ , or 3 heteroatoms ("heteroCi_6 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and ₁ or 2 heteroatoms ("heteroCi_5 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and ₁ or 2 heteroatoms ("heteroCi_4 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 _to 3 carbon atoms and 1 heteroatom ("heteroCi_3 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having ₁ to 2 carbon atoms and 1 heteroatom ("heteroCi_2 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (" _heteroCi alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC _2-6 alkyl"). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC _1-10 alkyl. In certain embodiments, a heteroalkyl group is a substituted heteroC _1-10 alkyl.

"Aryl" refers to the radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C _6-14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C ₆ aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C ₁₀ aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C ₁₄ aryl"; e.g., anthracyl). "Aryl" also includes ring systems, as defined above, in which the aryl ring is fused with one or more carbocyclyl or heterocyclyl groups, and the radical or point of attachment is on the aryl ring; in such instances, the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Exemplary aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, that is, unsubstituted (an "unsubstituted aryl") or substituted with one or more substituents (a "substituted aryl"). In certain embodiments, an aryl group is unsubstituted C _6-14 aryl. In certain embodiments, an aryl group is substituted C _6-14 aryl.

In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C _1-8 alkyl, C _1-8 haloalkyl, cyano, hydroxy, C _1-8 alkoxy, and amino.

Representative examples of substituted aryl include:
wherein one of R ⁵⁶ and R ⁵⁷ may be hydrogen; and at least one of R ⁵⁶ and R ⁵⁷ is each independently selected from C _1-8 alkyl, C _1-8 haloalkyl, 4- to 10-membered heterocyclyl, alkanoyl, C _1-8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR ⁵⁸ COR ⁵⁹ , NR 58 SOR 59 , NR ⁵⁸ SO ₂ R ⁵⁹ , COOalkyl ^, COOaryl, CONR ⁵⁸ R ⁵⁹ , CONR ⁵⁸ OR ⁵⁹ , NR ⁵⁸ R ⁵⁹ , SO ₂ NR ⁵⁸ R ⁵⁹ , S-alkyl, SO alkyl, SO ₂ ^alkyl , S aryl, SO aryl, SO ₂ aryl; or R ⁵⁶ and R ⁵⁷ can be joined to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from N, O, or S. R ⁶⁰ and R ⁶¹ are independently hydrogen, C _1-8 alkyl, C _1-4 haloalkyl, C _3-10 cycloalkyl, 4-10 membered heterocyclyl, C _6-10 aryl, substituted C _6-10 aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

"Fused aryl" refers to an aryl having two of its ring carbons common to a second aryl or heteroaryl ring, or a carbocyclic or heterocyclic ring.

"Heteroaryl" refers to the radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, the point of attachment being on the heteroaryl ring; in such instances, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment can be on either the aryl ring or the heteroaryl ring; in such cases, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring containing a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Representative examples of heteroaryls include:
wherein each Z is selected from carbonyl, N, NR ⁶⁵ , O, and S; and R ⁶⁵ is independently hydrogen, C _1-8 alkyl, C _3-10 cycloalkyl, 4-10 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl.

"Carbocyclyl" or "carbocyclic" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms (" _C3-10 carbocyclyl") and 0 heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (" _C3-8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (" _C3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (" _C3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (" _C5-10 carbocyclyl"). Exemplary _C3-6 carbocyclyl groups include, without limitation, cyclopropyl ( _C3 ), cyclopropenyl (C3), cyclobutyl ( _C4 ), cyclobutenyl ( _C4 ), cyclopentyl ( _C5 ), cyclopentenyl ( _C5 ), cyclohexyl ( _C6 ), cyclohexenyl ( _C6 ), cyclohexadienyl ( _C6 ) _, and the like. Exemplary _C3-8 carbocyclyl groups include, without limitation, the aforementioned _C3-6 carbocyclyl groups, as well as cycloheptyl ( _C7 ), cycloheptenyl ( _C7 ), cycloheptadienyl ( _C7 ), cycloheptatrienyl (C7), cyclooctyl ( _C8 ), cyclooctenyl ( _C8 ), bicyclo[2.2.1]heptanyl ( _C7 ), bicyclo[2.2.2]octanyl ( _C8 ) _, and the like. Exemplary C _3-10 carbocyclyl groups include, without limitation, the aforementioned C _3-8 carbocyclyl groups, as well as cyclononyl (C ₉ ), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H-indenyl (C ₉ ), decahydronaphthalenyl (C ₁₀ ), spiro[4.5]decanyl (C ₁₀ ), etc. As illustrated by the foregoing examples, in certain embodiments, a carbocyclyl group is either monocyclic (a "monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic system (a "bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring; in such instances, the number of carbons continues to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted with one or more substituents (a "substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted _C3-10 carbocyclyl. In certain embodiments, a carbocyclyl group is a substituted _C3-10 carbocyclyl.

In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms (" _{C3-10 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to} 8 ring carbon atoms (" _C3-8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (" _C3-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (" _C5-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (" _C5-10 cycloalkyl"). Examples of _C5-6 cycloalkyl groups include cyclopentyl ( _C5 ) and cyclohexyl ( _C5 ). Examples of _C3-6 cycloalkyl groups include the aforementioned _C5-6 cycloalkyl groups as well as cyclopropyl ( _C3 ) and cyclobutyl ( _C4 ). Examples of _C3-8 cycloalkyl groups include the aforementioned _C3-6 cycloalkyl groups, as well as cycloheptyl ( _C7 ) and cyclooctyl ( _C8 ). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted _{C3-10 cycloalkyl. In certain embodiments, a cycloalkyl group is a substituted C3-10 cycloalkyl} .

"Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heterocyclyl groups may be either monocyclic (a "monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems (a "bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups (the point of attachment is on either the carbocyclyl or heterocyclyl ring) or to one or more aryl or heteroaryl groups (the point of attachment is on the heterocyclyl ring); in such instances, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl group has 1 to 3 rings selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a _C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone, and piperazone.

"Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above hydrocarbyl groups, such as alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocyclyl), aryl (e.g., heteroaryl), and cycloalkenyl (e.g., cycloheteroalkenyl), having 1 to 5, especially 1 to 3, heteroatoms.

"Acyl" refers to the radical -C(O) ^R20 where ^R20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" is an acyl group where ^R20 is other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O) _CH3 ), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O) _CH2Ph ), --C(O) _-C1-8 alkyl, --C(O)-( _CH2 ) _t ( _C6-10 aryl), --C(O)-( _CH2 ) _t (5-10 membered heteroaryl), --C(O)-( _CH2 ) _t ( _C3-10 cycloalkyl), and --C(O)-( _CH2 ) _t (4-10 membered heterocyclyl), where t is an integer from 0 to 4. In certain embodiments, R ²¹ is C _1-8 alkyl substituted with halo or hydroxy, or C _3-10 cycloalkyl, 4-10 membered heterocyclyl, C _6-10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C _1-4 alkyl, halo, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 haloalkyl, unsubstituted C _{1-4 hydroxyalkyl, or unsubstituted C 1-4 haloalkoxy} or hydroxy.

"Alkoxy" refers to the group -OR ²⁹ , where R ²⁹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms. More particular alkoxy groups have 1 to 4 carbon atoms.

In certain embodiments, R ²⁹ is a group having one or more substituents, for example, 1 _{to 5} substituents, and particularly _{1 to 3 substituents, and especially 1 substituent, selected from the group consisting of amino, substituted amino, C 6-10 aryl, aryloxy, carboxyl, cyano, C 3-10} cycloalkyl, 4-10 membered heterocyclyl, halogen, _5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O) ₂ —, and aryl-S(O) 2 —. Exemplary "substituted alkoxy" groups include, but are not limited to, -O-( _CH2 ) _t ( _C6-10 aryl), -O- ₍ CH2) _t (5-10 membered heteroaryl), -O-( _CH2 ) _t ( _C3-10 cycloalkyl), and -O-( _CH2 ) _t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted by unsubstituted _C1-4 alkyl, halo, unsubstituted _C1-4 alkoxy, unsubstituted _C1-4 haloalkyl, unsubstituted _C1-4 hydroxyalkyl, or unsubstituted _C1-4 haloalkoxy or hydroxy. Certain exemplary "substituted alkoxy" groups are -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ Ph, -OCH ₂ -cyclopropyl, -OCH ₂ CH ₂ OH, and -OCH ₂ CH ₂ NMe ₂ .

"Amino" refers to the radical _-NH2 .

An "oxo group" refers to -C(=O)-.

"Substituted amino" refers to an amino group of the formula -N(R ³⁸ ) ₂ , where R ³⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, and at least one of R ³⁸ is not hydrogen. In certain embodiments, each R ³⁸ is independently selected from hydrogen, C _1-8 alkyl, C _3-8 alkenyl, C _3-8 alkynyl, C _6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C _3-10 cycloalkyl; or C _{1-8 alkyl substituted with halo or hydroxy; C 3-8} alkenyl substituted with halo or hydroxy, C _3-8 alkynyl substituted with halo or hydroxy, or —(CH ₂ ) _t (C _6-10 aryl), —(CH 2 ) t ( _5-10 membered heteroaryl), —(CH ₂ ) _t (C _{3-10 cycloalkyl), or —(CH 2 ) t (4-10 membered heterocyclyl )} , where _t is an integer from 0 to 8, and each is selected from unsubstituted C _1-4 alkyl, halo, unsubstituted C _1-4 alkoxy, unsubstituted C Substituted by _1-4 haloalkyl, unsubstituted C _1-4 hydroxyalkyl, or unsubstituted C _1-4 haloalkoxy or hydroxy, or both R ³⁸ are joined to form an alkylene group.

Exemplary "substituted amino" groups include, but are not limited to, -NR ³⁹ -C _1-8 alkyl, -NR ³⁹ -(CH ₂ ) _t (C _6-10 aryl), -NR ³⁹ -(CH ₂ ) _t (5-10 membered heteroaryl), -NR ³⁹ -(CH ₂ ) _t (C _3-10 cycloalkyl), and -NR ³⁹ -(CH ₂ ) _t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R ³⁹ independently represents H or C _1-8 alkyl, any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino, or hydroxy, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted by unsubstituted C _1-4 alkyl, halo, unsubstituted C _1-4 alkoxy, unsubstituted C It may be substituted by _1-4 haloalkyl, unsubstituted C _1-4 hydroxyalkyl, or unsubstituted C _1-4 haloalkyl or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino groups, substituted alkylamino groups, alkylarylamino groups, substituted alkylarylamino groups, arylamino groups, substituted arylamino groups, dialkylamino groups, and substituted dialkylamino groups as defined below. Substituted amino includes both mono- and di-substituted amino groups.

"Carboxy" refers to the radical -C(O)OH.

"Cyano" refers to the radical -CN.

"Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

"Haloalkyl" refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.

"Hydroxy" refers to the radical -OH.

"Nitro" refers to the radical _-NO2 .

"Thioketo" refers to the =S group.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not undergo spontaneous transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position in any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, among the substituents described herein, that result in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

Exemplary carbon atom substituents include halogen, —CN, —NO ₂ , —N ₃ , —SO ₂ H, —SO ₃ H, —OH, —OR ^aa , —ON(R ^bb ) ₂ , —N(R ^bb ) ₂ , —N(R ^bb ) ₃ ⁺ X ⁻ , —N(OR ^cc )R ^bb , —SH, —SR ^aa , —SSR ^cc , —C(═O)R ^aa , —CO ₂ H, —CHO, —C(OR ^cc ) ₂ , —CO ₂ R ^aa , —OC(═O)R ^aa , —OCO ₂ R ^aa , —C(═O)N(R ^bb ) ₂ , —OC(═O)N(R ^bb ) ₂ , —NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa , -Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(=S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , -P(=O) ₂ N(R ^bb ) ₂ , -OP(=O) ₂ N(R ^bb ) ₂ , -P(=O)(NR ^bb ) ₂ , -OP(=O)(NR ^bb ) ₂ , -NR ^bb P(=O)(OR ^cc ) ₂ , -NR ^bb P(=O)(NR ^bb ) ₂ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR ^aa (OR ^cc ), C _1-10 alkyl, C _{1-10 haloalkyl, C 2-10 alkenyl} , C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups, or two geminal hydrogens on the carbon atom are substituted with a group ═O, ═S, ═NN(R ^bb ) ₂ , ═NNR ^bb C(═O)R ^aa , ═NNR ^bb C(═O)OR ^aa , =NNR ^bb S(=O) ₂ R ^aa , =NR ^bb , or =NOR ^cc ;
each instance of R ^aa is independently selected from C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl; or two R ^aa groups joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;
Each example of R ^bb is independently hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O)(=NR ^cc ) ₂ , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl; or two R ^bb groups joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;
each instance of R ^cc is independently selected from hydrogen, C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3-10 carbocyclyl, 3-14} membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl; or two R ^cc groups joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;
Each instance of R ^dd is independently halogen, —CN, —NO ₂ , —N ₃ , —SO ₂ H, —SO ₃ H, —OH, —OR ^ee , —ON(R ^ff ) ₂ , —N(R ^ff ) ₂ , —N(R ^ff ) ₃ ⁺ X ⁻ , —N(OR ^ee )R ^ff , —SH, —SR ^ee , —SSR ^ee , —C(═O)R ^ee , —CO ₂ H, —CO ₂ R ^ee , —OC(═O)R ^ee , —OCO ₂ R ^ee , —C(═O)N(R ^ff ) ₂ , —OC(═O)N(R ^ff ) ₂ , —NR ^ff C(═O)R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C(=O)N(R ^ff ) ₂ , -C(=NR ^ff )OR ^ee , -OC(=NR ^ff )R ^ee , -OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff SO ₂ R ^ee , -SO ₂ N(R ^ff ) ₂ , -SO ₂ R ^ee , -SO ₂ OR ^ee , -OSO ₂ R ^ee , —S(═O)R ^ee , —Si(R ^ee ) ₃ , —OSi(R ^ee ) ₃ , —C(═S)N(R ^ff ) ₂ , —C(═O)SR ^ee , —C(═S)SR ^ee , —SC(═S)SR ^ee , —P(═O) ₂ R ^ee , —P(═O)(R ^ee ) ₂ , —OP(═O)(R ^ee ) ₂ , —OP(═O)(OR ^ee ) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C selected from _6-10 membered aryl, 5-10 membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl being independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups, or two geminal R ^dd substituents can be joined to form ═O or ═S;
each instance of R ^ee is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;
each instance of R ^ff is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl; or two R ^ff groups joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;
Each instance of R ^gg is independently halogen, —CN, —NO ₂ , —N ₃ , —SO ₂ H, —SO ₃ H, —OH, —OC _1-6 alkyl, —ON(C _1-6 alkyl) ₂ , —N(C _1-6 alkyl) ₂ , —N(C _1-6 alkyl) ₃ ⁺ X ⁻ , —NH(C _1-6 alkyl) ₂ ⁺ X ⁻ , —NH ₂ (C _1-6 alkyl) ⁺ X ⁻ , —NH ₃ ⁺ X ⁻ , —N(OC _1-6 alkyl)(C _1-6 alkyl), —N(OH)(C _1-6 alkyl), —NH(OH), —SH, —SC _1-6 alkyl, —SS(C _1-6 alkyl), —C(═O)(C _1-6 alkyl), —CO ₂ H, —CO ₂ (C _1-6 alkyl), -OC(=O)(C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C(=O)NH ₂ , -C(=O)N(C _1-6 alkyl) ₂ , -OC(=O)NH(C _1-6 alkyl), -NHC(=O)(C _1-6 alkyl), -N(C _1-6 alkyl)C(=O)(C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC(=O)N(C _1-6 alkyl) ₂ , -NHC(=O)NH(C _1-6 alkyl), -NHC(=O)NH ₂ , -C(=NH)O(C _1-6 alkyl), -OC(=NH)(C _1-6 alkyl), -OC(=NH)OC _1-6 alkyl, -C(=NH)N(C _1-6 alkyl) ₂ , -C(=NH)NH(C _1-6 alkyl), -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 alkyl) ₂ , -OC(NH)NH(C _1-6 alkyl), -OC(NH)NH ₂ , -NHC(NH)N(C _1-6 alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N(C _1-6 alkyl) ₂ , -SO ₂ NH(C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si(C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ , -C(=S)N(C _1-6 alkyl) ₂ , C(=S)NH(C _1-6 alkyl), C(=S)NH ₂ , -C(=O)S(C _1-6 alkyl), -C(=S)SC _1-6 alkyl, -SC(=S)SC _1-6 alkyl, -P(=O) ₂ (C _1-6 alkyl), -P(=O)(C _1-6 alkyl) ₂ , -OP(=O)(C _1-6 alkyl) ₂ , -OP(=O)(OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, or two geminal R ^gg substituents can be joined to form =0 or =S, and X ^- is a counterion.

A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electron neutrality. Exemplary counterions include halides (e.g., F ⁻ , Cl ⁻ , Br ⁻ , I ⁻ ), NO ₃ ⁻ , ClO ₄ ⁻ , OH ⁻ , H ₂ PO ₄ ⁻ , HSO ₄ ⁻ , sulfonates (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), and carboxylates (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

These and other exemplary substituents are described in further detail in the detailed description and claims. The present invention is not intended to be limited in any way by the above list of exemplary substituents.

Other Definitions As used herein, the term "modulation" refers to the inhibition or enhancement of GABA _A receptor function. A "modulator" (e.g., a modulating compound) can be, for example, an agonist, partial agonist, antagonist, or partial antagonist of a GABA _A receptor.

"Pharmaceutically acceptable" means approved or approvable by a regulatory agency of a federal or state government or its equivalent in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals, or more specifically, in humans.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specific examples of such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or salts formed with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoic acid)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or an equivalent with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts include, by way of example only, salts of non-toxic organic or inorganic acids such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, for example, Berge, et al., J. Pharm. Sci. (1977) 66(1):1-79.

The term "prodrug" is intended to encompass therapeutically inactive compounds that are converted under physiological conditions into the therapeutically active agents of the present invention. One method for creating a prodrug is to design a selected moiety that is hydrolyzed or cleaved at the targeted in vivo site of action under physiological conditions, revealing the desired molecule that then produces its therapeutic effect. In certain embodiments, the prodrug is converted by the enzymatic activity of the subject.

In an alternative embodiment, the present invention provides prodrugs of the compounds described herein, wherein the prodrugs include a cleavable moiety on the C3 hydroxy as shown in the formulas provided herein.

"Tautomers" refer to compounds that are interchangeable forms of a particular compound structure and vary in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the shifting of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert upon treatment with either acid or base. Another example of tautomerism is phenylnitromethane, whose acetyl and nitro forms are also formed upon treatment with acid or base. Tautomeric forms can be relevant to achieving optimal chemical reactivity and biological activity of a desired compound.

"Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and/or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human ("human subject"). In certain embodiments, the subject is a non-human animal.

In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include -R ^aa , -N(R ^bb ) ₂ , -C(═O)SR ^aa , -C(═O)R ^aa , -CO ₂ R ^aa , -C(═O)N(R ^bb ) ₂ , -C(═NR ^bb )R ^aa , -C(═NR ^bb )OR ^aa , -C(═NR ^bb )N(R ^bb ) ₂ , -S(═O)R ^aa , -SO ₂ R ^aa , -Si(R ^aa ) ₃ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -P(═O) ₂ R ^aa , -P(═O)(R ^aa ) ₂ , and -P(═O)(OR ^cc ). ₂ , -P(=O) _2N (R ^bb ) ₂ , and -P(=O)(NR ^bb ) ₂ , where R ^aa , R ^bb , and R ^cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).

In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include -R ^aa , -N(R ^bb ) ₂ , -C(═O)SR ^aa , -C(═O)R ^aa , -CO ₂ R ^aa , -C(═O)N(R ^bb ) ₂ , -C(═NR ^bb )R ^aa , -C(═NR ^bb )OR ^aa , -C(═NR ^bb )N(R ^bb ) ₂ , -S(═O)R ^aa , -SO ₂ R ^aa , -Si(R ^aa ) ₃ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -P(═O) ₂ R ^aa , -P(═O)(R ^aa ) ₂ , -P(═O)(OR ^cc ) ₂ , -P(=O) _2N (R ^bb ) ₂ , and -P(=O)(NR ^bb ) ₂ , where R ^aa , R ^bb , and R ^cc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

In certain embodiments, the substituent present on a nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Examples of amino protecting groups include -OH, -OR ^aa , -N(R ^cc ) ₂ , -C(=O)R ^aa , -C(=O)OR ^aa , -C(=O)N(R ^cc ) ₂ , -S(=O) ₂ R ^aa , -C(=NR ^cc )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc ,C [0033] Examples of protecting groups include, but are not limited to _{, 1-10} alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 carbocyclyl, 3-14 membered heterocyclyl, _C6-14 aryl, and 5-14 membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 ^Rdd groups, and R ^aa , R ^bb , R ^cc , and R ^dd are as defined herein. Amino protecting groups are well known in the art and are described in detail in "Protecting Groups in Organic Synthesis," T. W. Greene and P. G. M., "Protecting Groups in Organic Synthesis," by ... Wuts, 3rd edition, John Wiley & Sons, 1999.

Exemplary amino-protecting groups include, but are not limited to, amide groups (e.g., —C(═O)R ^aa ), including, but not limited to, formamide and acetamide; carbamate groups (e.g., —C(═O)OR ^aa ), including, but not limited to, 9-fluorenylmethylcarbamate (Fmoc), t-butylcarbamate (BOC), and benzylcarbamate (Cbz); sulfonamide groups (e.g., —S(═O) ₂ R ^aa ), including, but not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

Disease, disorder, and condition are used interchangeably herein.

As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with the specified disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject begins to suffer from the specified disease, disorder, or condition.

In general, an "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a CNS-related disorder, such as sufficient to induce anesthesia or sedation. As will be understood by one of skill in the art, the effective amount of a compound of the invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.

As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

In an alternative embodiment, the present invention contemplates administering a compound of the present invention, or a pharmaceutically acceptable salt or composition thereof, as a prophylactic agent before a subject begins to suffer from a particular disease, disorder, or condition. As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

Compounds It is understood that the formulas set forth herein may refer to specific carbon atoms, such as C17, C3, C19, etc. These references are based on the position of the carbon atoms according to steroid nomenclature known and used in the industry, as shown below.
For example, C17 refers to the 17th carbon, and C3 refers to the 3rd carbon.

In one aspect, provided herein are compounds of formula I:
or a pharmaceutically acceptable salt thereof,
During the ceremony,
represents a single or double bond, provided that when a double bond is present, one of R ^6a or R ^6b is absent and R ⁵ is absent;
R ^X is selected from the group consisting of halo, —OH, —OR ^Q1 , and substituted or unsubstituted alkyl, and R ^Q1 is substituted or unsubstituted alkyl;
R 1 ^Y is halo, or substituted or unsubstituted alkyl, or R 1 ^Y and R 1 ^X , together with the intervening atoms, can join to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
^R3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
^R5 is hydrogen or methyl;
Each instance of R ²² is independently halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —OC(═O)R ^GA , —OC(═O)OR ^GA , —C(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)R ^GA , —OC(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)OR ^GA , —N(R ^GA )C(═O)N(R ^GA ) ₂ , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ OR ^GA , —OS(═O) ₂ R ^GA , —S(═O) ₂ N(R ^GA ) ₂ , —N(R ^GA )S(═O) ₂ R ^GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R ^GA is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C _3-6 carbosilyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^{the GA} groups together with the intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
Each of R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a and R ^12b is independently hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^A1 , —N(R ^A1 ) ₂ , —SR ^A1 , —C(═O)R ^A1 , —C(═O)OR ^A1 , —C(═O)SR ^A1 , —C(═O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N(R ^A1 ) ₂ , -N(R ^A1 )C(=O)R ^A1 , -N(R ^A1 )C(=NR ^A1 )R ^A1 , -N(R ^A1 )C(=O)OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 )C(=NR ^A1 )N(R ^A1 ) ₂ , -N(R ^A1 )S(=O) ₂ R ^A1 , —N(R ^A1 )S(═O) ₂ OR ^A1 , —N(R ^A1 )S(═O) ₂ N(R ^A1 ) ₂ , —SC(═O)R ^A1 , —SC(═O)OR ^A1 , —SC(═O)SR ^A1 , —SC(═O)N(R ^A1 ) ₂ , —S(═O) ₂ R ^A1 , —S(═O) ₂ OR ^A1 , or —S(═O) ₂ N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, or substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups together with intervening atoms form a substituted or unsubstituted heterocyclic ring;
each of R ^6a and R ^6b is independently selected from the group consisting of hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b are joined to form an oxo (═O) group;
Each of R ^15a , R ^15b , R ^16a and R ^16b is independently hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^C3 , —N(R ^C3 ) ₂ , —SR ^C3 , —C(═O)R ^C3 , —C(═O)OR ^C3 , —C(═O)SR ^C3 , —C(═O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , —OC(═O)OR ^C3 , —OC(═O)N(R ^C3 ) ₂ , —OC(═O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N(R ^C3 ) ₂ , -N(R ^C3 )C(=O)R ^C3 , -N(R ^C3 )C(=NR ^C3 )R ^C3 , -N(R ^C3 )C(=O)OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 )C(=NR ^C3 )N(R ^C3 ) ₂ , -N(R ^C3 )S(=O) ₂ R ^C3 , -N(R ^C3 )S(=O) ₂ OR ^C3 , -N(R ^C3 )S(=O) ₂ N(R ^C3 ) ₂ , —SC(═O)R ^C3 , —SC(═O)OR ^C3 , —SC(═O)SR ^C3 , —SC(═O)N(R ^C3 ) ₂ , —S(═O) _2R ^C3 , —S(═O) _2OR ^C3 , or —S(═O) _2N (R ^C3 ) ₂ , wherein each instance of R ^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; or two R ^{the C3} groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen or substituted or unsubstituted alkyl;
n is 0, 1, 2, or 3;
t is 2 or 3.

In certain aspects, provided herein are compounds of formula II:
or a pharmaceutically acceptable salt thereof,
During the ceremony,
represents a single or double bond, provided that when a double bond is present, one of R ^6a or R ^6b is absent and R ⁵ is absent;
R ^X is selected from the group consisting of halo, —OH, —OR ^Q1 , and substituted or unsubstituted alkyl, and R ^Q1 is substituted or unsubstituted alkyl;
R 1 ^Y is halo, or substituted or unsubstituted alkyl, or R 1 ^Y and R 1 ^X , together with the intervening atoms, can join to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
^R3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
^R5 is hydrogen or methyl;
Each instance of R ²² is independently halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —OC(═O)R ^GA , —OC(═O)OR ^GA , —C(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)R ^GA , —OC(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)OR ^GA , —N(R ^GA )C(═O)N(R ^GA ) ₂ , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ OR ^GA , —OS(═O) ₂ R ^GA , —S(═O) ₂ N(R ^GA ) ₂ , —N(R ^GA )S(═O) ₂ R ^GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R ^GA is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C _3-6 carbosilyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^{the GA} groups together with the intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
Each of R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a and R ^12b is independently hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^A1 , —N(R ^A1 ) ₂ , —SR ^A1 , —C(═O)R ^A1 , —C(═O)OR ^A1 , —C(═O)SR ^A1 , —C(═O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N(R ^A1 ) ₂ , -N(R ^A1 )C(=O)R ^A1 , -N(R ^A1 )C(=NR ^A1 )R ^A1 , -N(R ^A1 )C(=O)OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 )C(=NR ^A1 )N(R ^A1 ) ₂ , -N(R ^A1 )S(=O) ₂ R ^A1 , —N(R ^A1 )S(═O) ₂ OR ^A1 , —N(R ^A1 )S(═O) ₂ N(R ^A1 ) ₂ , —SC(═O)R ^A1 , —SC(═O)OR ^A1 , —SC(═O)SR ^A1 , —SC(═O)N(R ^A1 ) ₂ , —S(═O) ₂ R ^A1 , —S(═O) ₂ OR ^A1 , or —S(═O) ₂ N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, or substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups together with intervening atoms form a substituted or unsubstituted heterocyclic ring;
each of R ^6a and R ^6b is independently selected from the group consisting of hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b are joined to form an oxo (═O) group;
Each of R ^15a , R ^15b , R ^16a and R ^16b is independently hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^C3 , —N(R ^C3 ) ₂ , —SR ^C3 , —C(═O)R ^C3 , —C(═O)OR ^C3 , —C(═O)SR ^C3 , —C(═O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , —OC(═O)OR ^C3 , —OC(═O)N(R ^C3 ) ₂ , —OC(═O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N(R ^C3 ) ₂ , -N(R ^C3 )C(=O)R ^C3 , -N(R ^C3 )C(=NR ^C3 )R ^C3 , -N(R ^C3 )C(=O)OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 )C(=NR ^C3 )N(R ^C3 ) ₂ , -N(R ^C3 )S(=O) ₂ R ^C3 , -N(R ^C3 )S(=O) ₂ OR ^C3 , -N(R ^C3 )S(=O) ₂ N(R ^C3 ) ₂ , —SC(═O)R ^C3 , —SC(═O)OR ^C3 , —SC(═O)SR ^C3 , —SC(═O)N(R ^C3 ) ₂ , —S(═O) _2R ^C3 , —S(═O) _2OR ^C3 , or —S(═O) _2N (R ^C3 ) ₂ , wherein each instance of R ^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; or two R ^{the C3} groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen or substituted or unsubstituted alkyl;
R ¹⁸ is substituted or unsubstituted alkyl;
n is 0, 1, 2, or 3,
With the proviso that when ^R5 is hydrogen, ^R18 is not _-CH3 .

In some embodiments, the compound of Formula II is a compound of Formula IIIa or IIIb:
or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein are compounds of formula V:
or a pharmaceutically acceptable salt thereof,
During the ceremony,
represents a single or double bond, provided that when a double bond is present, one of R ^6a or R ^6b is absent and R ⁵ is absent;
R ^X is selected from the group consisting of halo, —OH, —OR ^Q1 , and substituted or unsubstituted alkyl, and R ^Q1 is substituted or unsubstituted alkyl;
R 1 ^Y is halo, or substituted or unsubstituted alkyl, or R 1 ^Y and R 1 ^X , together with the intervening atoms, can join to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
^R3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
^R5 is hydrogen or methyl;
Each instance of R ²² is independently halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —OC(═O)R ^GA , —OC(═O)OR ^GA , —C(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)R ^GA , —OC(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)OR ^GA , —N(R ^GA )C(═O)N(R ^GA ) ₂ , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ OR ^GA , —OS(═O) ₂ R ^GA , —S(═O) ₂ N(R ^GA ) ₂ , —N(R ^GA )S(═O) ₂ R ^GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R ^GA is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C _3-6 carbosilyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^{the GA} groups together with the intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
Each of R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a and R ^12b is independently hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^A1 , —N(R ^A1 ) ₂ , —SR ^A1 , —C(═O)R ^A1 , —C(═O)OR ^A1 , —C(═O)SR ^A1 , —C(═O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N(R ^A1 ) ₂ , -N(R ^A1 )C(=O)R ^A1 , -N(R ^A1 )C(=NR ^A1 )R ^A1 , -N(R ^A1 )C(=O)OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 )C(=NR ^A1 )N(R ^A1 ) ₂ , -N(R ^A1 )S(=O) ₂ R ^A1 , —N(R ^A1 )S(═O) ₂ OR ^A1 , —N(R ^A1 )S(═O) ₂ N(R ^A1 ) ₂ , —SC(═O)R ^A1 , —SC(═O)OR ^A1 , —SC(═O)SR ^A1 , —SC(═O)N(R ^A1 ) ₂ , —S(═O) ₂ R ^A1 , —S(═O) ₂ OR ^A1 , or —S(═O) ₂ N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, or substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups together with intervening atoms form a substituted or unsubstituted heterocyclic ring;
each of R ^6a and R ^6b is independently selected from the group consisting of hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b are joined to form an oxo (═O) group;
Each of R ^15a or R ^15b is independently hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^C3 , —N(R ^C3 ) ₂ , —SR ^C3 , —C(═O)R ^C3 , —C(═O)OR ^C3 , —C(═O)SR ^C3 , —C(═O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , —OC(═O)OR ^C3 , —OC(═O)N(R ^C3 ) ₂ , —OC(═O)SR ^C3 , —OS(═O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N(R ^C3 ) ₂ , -N(R ^C3 )C(=O)R ^C3 , -N(R ^C3 )C(=NR ^C3 )R ^C3 , -N(R ^C3 )C(=O)OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 )C(=NR ^C3 )N(R ^C3 ) ₂ , -N(R ^C3 )S(=O) ₂ R ^C3 , -N(R ^C3 )S(=O) ₂ OR ^C3 , -N(R ^C3 )S(=O) ₂ N(R ^C3 ) ₂ , —SC(═O)R ^C3 , —SC(═O)OR ^C3 , —SC(═O)SR ^C3 , —SC(═O)N(R ^C3 ) ₂ , —S(═O) _2R ^C3 , —S(═O) _2OR ^C3 , or —S(═O) _2N (R ^C3 ) ₂ , wherein each instance of R ^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^{the C3} groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen or substituted or unsubstituted alkyl;
n is 0, 1, 2, or 3.

In certain aspects, provided herein are compounds of formula VIa or VIb:
or a pharmaceutically acceptable salt thereof,
During the ceremony,
represents a single or double bond, provided that when a double bond is present, one of R ^6a or R ^6b is absent and R ⁵ is absent;
R ^X is selected from the group consisting of halo, —OH, —OR ^Q1 , and substituted or unsubstituted alkyl, and R ^Q1 is substituted or unsubstituted alkyl;
R 1 ^Y is halo, or substituted or unsubstituted alkyl, or R 1 ^Y and R 1 ^X , together with the intervening atoms, can join to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
^R3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
^R5 is hydrogen or methyl;
Each instance of R ²² is independently halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —OC(═O)R ^GA , —OC(═O)OR ^GA , —C(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)R ^GA , —OC(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)OR ^GA , —N(R ^GA )C(═O)N(R ^GA ) ₂ , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ OR ^GA , —OS(═O) ₂ R ^GA , —S(═O) ₂ N(R ^GA ) ₂ , —N(R ^GA )S(═O) ₂ R ^GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R ^GA is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C _3-6 carbosilyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^{the GA} groups together with the intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
Each of R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a and R ^12b is independently hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^A1 , —N(R ^A1 ) ₂ , —SR ^A1 , —C(═O)R ^A1 , —C(═O)OR ^A1 , —C(═O)SR ^A1 , —C(═O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N(R ^A1 ) ₂ , -N(R ^A1 )C(=O)R ^A1 , -N(R ^A1 )C(=NR ^A1 )R ^A1 , -N(R ^A1 )C(=O)OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 )C(=NR ^A1 )N(R ^A1 ) ₂ , -N(R ^A1 )S(=O) ₂ R ^A1 , —N(R ^A1 )S(═O) ₂ OR ^A1 , —N(R ^A1 )S(═O) ₂ N(R ^A1 ) ₂ , —SC(═O)R ^A1 , —SC(═O)OR ^A1 , —SC(═O)SR ^A1 , —SC(═O)N(R ^A1 ) ₂ , —S(═O) ₂ R ^A1 , —S(═O) ₂ OR ^A1 , or —S(═O) ₂ N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, or substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups together with intervening atoms form a substituted or unsubstituted heterocyclic ring;
each of R ^6a and R ^6b is independently selected from the group consisting of hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b are joined to form an oxo (═O) group;
Each of R ^15a , R ^15b , R ^16a and R ^16b is independently hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^C3 , —N(R ^C3 ) ₂ , —SR ^C3 , —C(═O)R ^C3 , —C(═O)OR ^C3 , —C(═O)SR ^C3 , —C(═O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , —OC(═O)OR ^C3 , —OC(═O)N(R ^C3 ) ₂ , —OC(═O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N(R ^C3 ) ₂ , -N(R ^C3 )C(=O)R ^C3 , -N(R ^C3 )C(=NR ^C3 )R ^C3 , -N(R ^C3 )C(=O)OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 )C(=NR ^C3 )N(R ^C3 ) ₂ , -N(R ^C3 )S(=O) ₂ R ^C3 , -N(R ^C3 )S(=O) ₂ OR ^C3 , -N(R ^C3 )S(=O) ₂ N(R ^C3 ) ₂ , —SC(═O)R ^C3 , —SC(═O)OR ^C3 , —SC(═O)SR ^C3 , —SC(═O)N(R ^C3 ) ₂ , —S(═O) _2R ^C3 , —S(═O) _2OR ^C3 , or —S(═O) _2N (R ^C3 ) ₂ , wherein each instance of R ^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; or two R ^{the C3} groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen or substituted or unsubstituted alkyl;
r is 2 or 3;
p is 2 or 3;
n is 0, 1, 2, or 3.

In certain aspects, provided herein are compounds of formula VII:
or a pharmaceutically acceptable salt thereof,
During the ceremony,
represents a single or double bond, provided that when a double bond is present, one of R ^6a or R ^6b is absent and R ⁵ is absent;
R ^X is selected from the group consisting of halo, —OH, —OR ^Q1 , and substituted or unsubstituted alkyl, and R ^Q1 is substituted or unsubstituted alkyl;
R 1 ^Y is halo, or substituted or unsubstituted alkyl, or R 1 ^Y and R 1 ^X , together with the intervening atoms, can join to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
^R3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
^R5 is hydrogen or methyl;
Each instance of R ²² is independently halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —OC(═O)R ^GA , —OC(═O)OR ^GA , —C(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)R ^GA , —OC(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)OR ^GA , —N(R ^GA )C(═O)N(R ^GA ) ₂ , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ OR ^GA , —OS(═O) ₂ R ^GA , —S(═O) ₂ N(R ^GA ) ₂ , —N(R ^GA )S(═O) ₂ R ^GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R ^GA is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C _3-6 carbosilyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^{the GA} groups together with the intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
each of R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a and R ^12b independently represents hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^A1 , —N(R ^A1 ) ₂ , —SR ^A1 , —C(═O)R ^A1 , —C(═O)OR ^A1 , —C(═O)SR ^A1 , —C(═O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , —OC(═O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N(R ^A1 ) ₂ , -N(R ^A1 )C(=O)R ^A1 , -N(R ^A1 )C(=NR ^A1 )R ^A1 , -N(R ^A1 )C(=O)OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 )C(=NR ^A1 )N(R ^A1 ) ₂ , -N(R ^A1 )S(=O) ₂ R ^A1 , -N(R ^A1 )S(=O) ₂ OR ^A1 , —N(R ^A1 )S(=O) ₂ N(R ^A1 ) ₂ , —SC(=O)R ^A1 , —SC(=O)OR ^A1 , —SC(=O)SR ^A1 , —SC(=O)N(R ^A1 ) ₂ , —S(=O) ₂ R ^A1 , —S(=O) ₂ OR ^A1 , or —S(=O) ₂ N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, or substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups together with intervening atoms form a substituted or unsubstituted heterocyclic ring;
each of R ^6a and R ^6b is independently selected from the group consisting of hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b are joined to form an oxo (═O) group;
Each of R ^15a , R ^15b , R ^16a and R ^16b is independently hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^C3 , —N(R ^C3 ) ₂ , —SR ^C3 , —C(═O)R ^C3 , —C(═O)OR ^C3 , —C(═O)SR ^C3 , —C(═O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , —OC(═O)OR ^C3 , —OC(═O)N(R ^C3 ) ₂ , —OC(═O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N(R ^C3 ) ₂ , -N(R ^C3 )C(=O)R ^C3 , -N(R ^C3 )C(=NR ^C3 )R ^C3 , -N(R ^C3 )C(=O)OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 )C(=NR ^C3 )N(R ^C3 ) ₂ , -N(R ^C3 )S(=O) ₂ R ^C3 , -N(R ^C3 )S(=O) ₂ OR ^C3 , -N(R ^C3 )S(=O) ₂ N(R ^C3 ) ₂ , —SC(═O)R ^C3 , —SC(═O)OR ^C3 , —SC(═O)SR ^C3 , —SC(═O)N(R ^C3 ) ₂ , —S(═O) _2R ^C3 , —S(═O) _2OR ^C3 , or —S(═O) _2N (R ^C3 ) ₂ , wherein each instance of R ^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; or two R ^{the C3} groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen or substituted or unsubstituted alkyl;
n is 0, 1, 2, or 3.

In certain aspects, provided herein are compounds of Formula VIII:
or a pharmaceutically acceptable salt thereof,
During the ceremony,
represents a single or double bond, provided that when a double bond is present, one of R ^6a or R ^6b is absent and R ⁵ is absent;
R ^X is selected from the group consisting of halo, —OH, —OR ^Q1 , and substituted or unsubstituted alkyl, and R ^Q1 is substituted or unsubstituted alkyl;
R 1 ^Y is halo, or substituted or unsubstituted alkyl, or R 1 ^Y and R 1 ^X , together with the intervening atoms, can join to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
^R3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
^R5 is hydrogen or methyl;
Each instance of R ²² is independently halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —OC(═O)R ^GA , —OC(═O)OR ^GA , —C(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)R ^GA , —OC(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)OR ^GA , —N(R ^GA )C(═O)N(R ^GA ) ₂ , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ OR ^GA , —OS(═O) ₂ R ^GA , —S(═O) ₂ N(R ^GA ) ₂ , —N(R ^GA )S(═O) ₂ R ^GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R ^GA is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C _3-6 carbosilyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^{the GA} groups together with the intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
Each of R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a and R ^12b is independently hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^A1 , —N(R ^A1 ) ₂ , —SR ^A1 , —C(═O)R ^A1 , —C(═O)OR ^A1 , —C(═O)SR ^A1 , —C(═O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N(R ^A1 ) ₂ , -N(R ^A1 )C(=O)R ^A1 , -N(R ^A1 )C(=NR ^A1 )R ^A1 , -N(R ^A1 )C(=O)OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 )C(=NR ^A1 )N(R ^A1 ) ₂ , -N(R ^A1 )S(=O) ₂ R ^A1 , —N(R ^A1 )S(═O) ₂ OR ^A1 , —N(R ^A1 )S(═O) ₂ N(R ^A1 ) ₂ , —SC(═O)R ^A1 , —SC(═O)OR ^A1 , —SC(═O)SR ^A1 , —SC(═O)N(R ^A1 ) ₂ , —S(═O) ₂ R ^A1 , —S(═O) ₂ OR ^A1 , or —S(═O) ₂ N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, or substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups together with intervening atoms form a substituted or unsubstituted heterocyclic ring;
each of R ^6a and R ^6b is independently selected from the group consisting of hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b are joined to form an oxo (═O) group;
Each of R ^15a , R ^15b , R ^16a and R ^16b is independently hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^C3 , —N(R ^C3 ) ₂ , —SR ^C3 , —C(═O)R ^C3 , —C(═O)OR ^C3 , —C(═O)SR ^C3 , —C(═O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , —OC(═O)OR ^C3 , —OC(═O)N(R ^C3 ) ₂ , —OC(═O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N(R ^C3 ) ₂ , -N(R ^C3 )C(=O)R ^C3 , -N(R ^C3 )C(=NR ^C3 )R ^C3 , -N(R ^C3 )C(=O)OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 )C(=NR ^C3 )N(R ^C3 ) ₂ , -N(R ^C3 )S(=O) ₂ R ^C3 , -N(R ^C3 )S(=O) ₂ OR ^C3 , -N(R ^C3 )S(=O) ₂ N(R ^C3 ) ₂ , —SC(═O)R ^C3 , —SC(═O)OR ^C3 , —SC(═O)SR ^C3 , —SC(═O)N(R ^C3 ) ₂ , —S(═O) _2R ^C3 , —S(═O) _2OR ^C3 , or —S(═O) _2N (R ^C3 ) ₂ , wherein each instance of R ^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; or two R ^{the C3} groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen or substituted or unsubstituted alkyl;
s is 2,
n is 0, 1, 2, or 3.

In some embodiments, provided herein are compounds of formula IX:
or a pharmaceutically acceptable salt thereof,
During the ceremony,
R ^X is selected from the group consisting of halo, —OH, —OR ^Q1 , and substituted or unsubstituted alkyl, and R ^Q1 is substituted or unsubstituted alkyl;
R 1 ^Y is halo, or substituted or unsubstituted alkyl, or R 1 ^Y and R 1 ^X , together with the intervening atoms, can join to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
^R3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
^R5 is hydrogen or methyl;
Each instance of R ²² is independently halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —OC(═O)R ^GA , —OC(═O)OR ^GA , —C(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)R ^GA , —OC(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)OR ^GA , —N(R ^GA )C(═O)N(R ^GA ) ₂ , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ OR ^GA , —OS(═O) ₂ R ^GA , —S(═O) ₂ N(R ^GA ) ₂ , —N(R ^GA )S(═O) ₂ R ^GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R ^GA is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C _3-6 carbosilyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^{the GA} groups together with the intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
Each of R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a and R ^12b is independently hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^A1 , —N(R ^A1 ) ₂ , —SR ^A1 , —C(═O)R ^A1 , —C(═O)OR ^A1 , —C(═O)SR ^A1 , —C(═O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N(R ^A1 ) ₂ , -N(R ^A1 )C(=O)R ^A1 , -N(R ^A1 )C(=NR ^A1 )R ^A1 , -N(R ^A1 )C(=O)OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 )C(=NR ^A1 )N(R ^A1 ) ₂ , -N(R ^A1 )S(=O) ₂ R ^A1 , —N(R ^A1 )S(═O) ₂ OR ^A1 , —N(R ^A1 )S(═O) ₂ N(R ^A1 ) ₂ , —SC(═O)R ^A1 , —SC(═O)OR ^A1 , —SC(═O)SR ^A1 , —SC(═O)N(R ^A1 ) ₂ , —S(═O) ₂ R ^A1 , —S(═O) ₂ OR ^A1 , or —S(═O) ₂ N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, or substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups together with intervening atoms form a substituted or unsubstituted heterocyclic ring;
Each of R ^15a , R ^15b , R ^16a and R ^16b is independently hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^C3 , —N(R ^C3 ) ₂ , —SR ^C3 , —C(═O)R ^C3 , —C(═O)OR ^C3 , —C(═O)SR ^C3 , —C(═O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , —OC(═O)OR ^C3 , —OC(═O)N(R ^C3 ) ₂ , —OC(═O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N(R ^C3 ) ₂ , -N(R ^C3 )C(=O)R ^C3 , -N(R ^C3 )C(=NR ^C3 )R ^C3 , -N(R ^C3 )C(=O)OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 )C(=NR ^C3 )N(R ^C3 ) ₂ , -N(R ^C3 )S(=O) ₂ R ^C3 , -N(R ^C3 )S(=O) ₂ OR ^C3 , -N(R ^C3 )S(=O) ₂ N(R ^C3 ) ₂ , —SC(═O)R ^C3 , —SC(═O)OR ^C3 , —SC(═O)SR ^C3 , —SC(═O)N(R ^C3 ) ₂ , —S(═O) _2R ^C3 , —S(═O) _2OR ^C3 , or —S(═O) _2N (R ^C3 ) ₂ , wherein each instance of R ^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; or two R ^{the C3} groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen or substituted or unsubstituted alkyl;
n is 0, 1, 2, or 3.

In certain aspects, provided herein are compounds of formula X:
or a pharmaceutically acceptable salt thereof,
During the ceremony,
represents a single or double bond, provided that when a double bond is present, one of R ^6a or R ^6b is absent and R ⁵ is absent;
R ^X is selected from the group consisting of halo, —OH, —OR ^Q1 , and substituted or unsubstituted alkyl, and R ^Q1 is substituted or unsubstituted alkyl;
R 1 ^Y is halo, or substituted or unsubstituted alkyl, or R 1 ^Y and R 1 ^X , together with the intervening atoms, can join to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
^R3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
^R5 is hydrogen or methyl;
Each instance of R ²² is independently halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —OC(═O)R ^GA , —OC(═O)OR ^GA , —C(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)R ^GA , —OC(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)OR ^GA , —N(R ^GA )C(═O)N(R ^GA ) ₂ , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ OR ^GA , —OS(═O) ₂ R ^GA , —S(═O) ₂ N(R ^GA ) ₂ , —N(R ^GA )S(═O) ₂ R ^GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R ^GA is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C _3-6 carbosilyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^{the GA} groups together with the intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
Each of R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a and R ^12b is independently hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^A1 , —N(R ^A1 ) ₂ , —SR ^A1 , —C(═O)R ^A1 , —C(═O)OR ^A1 , —C(═O)SR ^A1 , —C(═O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N(R ^A1 ) ₂ , -N(R ^A1 )C(=O)R ^A1 , -N(R ^A1 )C(=NR ^A1 )R ^A1 , -N(R ^A1 )C(=O)OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 )C(=NR ^A1 )N(R ^A1 ) ₂ , -N(R ^A1 )S(=O) ₂ R ^A1 , —N(R ^A1 )S(═O) ₂ OR ^A1 , —N(R ^A1 )S(═O) ₂ N(R ^A1 ) ₂ , —SC(═O)R ^A1 , —SC(═O)OR ^A1 , —SC(═O)SR ^A1 , —SC(═O)N(R ^A1 ) ₂ , —S(═O) ₂ R ^A1 , —S(═O) ₂ OR ^A1 , or —S(═O) ₂ N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, or substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups together with intervening atoms form a substituted or unsubstituted heterocyclic ring;
each of R ^6a and R ^6b is independently selected from the group consisting of hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b are joined to form an oxo (═O) group;
Each of R ^15a , R ^15b , R ^16a and R ^16b is independently hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^C3 , —N(R ^C3 ) ₂ , —SR ^C3 , —C(═O)R ^C3 , —C(═O)OR ^C3 , —C(═O)SR ^C3 , —C(═O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , —OC(═O)OR ^C3 , —OC(═O)N(R ^C3 ) ₂ , —OC(═O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N(R ^C3 ) ₂ , -N(R ^C3 )C(=O)R ^C3 , -N(R ^C3 )C(=NR ^C3 )R ^C3 , -N(R ^C3 )C(=O)OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 )C(=NR ^C3 )N(R ^C3 ) ₂ , -N(R ^C3 )S(=O) ₂ R ^C3 , -N(R ^C3 )S(=O) ₂ OR ^C3 , -N(R ^C3 )S(=O) ₂ N(R ^C3 ) ₂ , —SC(═O)R ^C3 , —SC(═O)OR ^C3 , —SC(═O)SR ^C3 , —SC(═O)N(R ^C3 ) ₂ , —S(═O) _2R ^C3 , —S(═O) _2OR ^C3 , or —S(═O) _2N (R ^C3 ) ₂ , wherein each instance of R ^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; or two R ^{the C3} groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen or substituted or unsubstituted alkyl;
q is 2,
n is 0, 1, 2, or 3.

R ^1a and R ^1b Groups In some embodiments, each of R ^1a and R ^1b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -C(=O)R ^A1 , -C(=O)OR ^A1 , or -C(=O)N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^1a and R ^1b is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, or —OR ^A1 , and each instance of R ^A1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^1a and R ^1b is independently hydrogen, unsubstituted C _1-6 alkyl, C _1-3 haloalkyl, or —OR ^A1 , where R ^A1 is hydrogen or unsubstituted alkyl.

In some embodiments, each of R ^1a and R ^1b is independently hydrogen or substituted or unsubstituted C _1-6 alkyl.

In some embodiments, R ^1a and R ^1b are each independently hydrogen.

In some embodiments, R ^1a and R ^1b are both hydrogen.
R ^2a and R ^2b groups

In some embodiments, each of R ^2a and R ^2b is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -C(=O)R ^A1 , -C(=O)OR ^A1 , or -C(=O)N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^2a and R ^2b is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, or —OR ^A1 , and each instance of R ^A1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^2a and R ^2b is independently hydrogen, unsubstituted C _1-6 alkyl, C _1-3 haloalkyl, or —OR ^A1 , where R ^A1 is hydrogen or unsubstituted alkyl.

In some embodiments, R ^2a and R ^2b are each independently hydrogen.

In some embodiments, R ^2a and R ^2b are both hydrogen.

R ^4a and R ^4b Groups In some embodiments, R ^4a and R ^4b are each independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -C(=O)R ^A1 , -C(=O)OR ^A1 , or -C(=O)N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^4a and R ^4b is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, or —OR ^A1 , and each instance of R ^A1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^4a and R ^4b is independently hydrogen, unsubstituted C _1-6 alkyl, C _1-3 haloalkyl, or —OR ^A1 , where R ^A1 is hydrogen or unsubstituted alkyl.

In some embodiments, R ^4a and R ^4b are each independently hydrogen.

In some embodiments, R ^4a and R ^4b are both hydrogen.

R ^7a and R ^7b Groups In some embodiments, each of R ^7a and R ^7b is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -C(=O)R ^A1 , -C(=O)OR ^A1 , or -C(=O)N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^7a and R ^7b is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, or —OR ^A1 , and each instance of R ^A1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^7a and R ^7b is independently hydrogen, unsubstituted C _1-6 alkyl, C _1-3 haloalkyl, or —OR ^A1 , where R ^A1 is hydrogen or unsubstituted alkyl.

In some embodiments, R ^7a and R ^7b are each independently hydrogen.

In some embodiments, R ^7a and R ^7b are both hydrogen.

R ^11a and R ^11b Groups In some embodiments, each of R ^11a and R ^11b is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -C(═O)R ^A1 , -C(═O)OR ^A1 , or -C(═O)N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^11a and R ^11b is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, or —OR ^A1 , and each instance of R ^A1 is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^11a and R ^11b is independently hydrogen, unsubstituted C _1-6 alkyl, C _1-3 haloalkyl, or —OR ^A1 , where R ^A1 is hydrogen or unsubstituted alkyl.

In some embodiments, R ^11a and R ^11b are each independently hydrogen.

In some embodiments, R ^11a and R ^11b are both hydrogen.

R ^12a and R ^12b Groups In some embodiments, each of R ^12a and R ^12b is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -C(=O)R ^A1 , -C(=O)OR ^A1 , or -C(=O)N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^12a and R ^12b is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, or —OR ^A1 , and each instance of R ^A1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^12a and R ^12b is independently hydrogen, unsubstituted C _1-6 alkyl, C _1-3 haloalkyl, or —OR ^A1 , where R ^A1 is hydrogen or unsubstituted alkyl.

In some embodiments, each of R ^12a and R ^12b is independently hydrogen.

In some embodiments, R ^12a and R ^12b are both hydrogen.

R ^6a and R ^6b Groups In some embodiments, each of R ^6a and R ^6b is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

In some embodiments, each of R ^6a and R ^6b is independently hydrogen or substituted or unsubstituted alkyl.

In some embodiments, R ^6a and R ^6b are each independently hydrogen.

In some embodiments, R ^6a and R ^6b are both hydrogen.

R ^15a and R ^15b Groups In some embodiments, each of R ^15a and R ^15b is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^15a and R ^15b is independently hydrogen or substituted or unsubstituted alkyl.

In some embodiments, R ^15a and R ^15b are each independently hydrogen or unsubstituted alkyl.

In some embodiments, R ^15a and R ^15b are each independently hydrogen or unsubstituted C _1-6 alkyl.

In some embodiments, R ^15a and R ^15b are each independently hydrogen.

In some embodiments, R ^15a and R ^15b are each independently hydrogen.

In some embodiments, R ^15a and R ^15b are both hydrogen.

The Groups R ^16a and R ^16b In some embodiments, each of R ^16a and R ^16b is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R ^16a and R ^16b is independently hydrogen or substituted or unsubstituted alkyl.

In some embodiments, each of R ^16a and R ^16b is independently hydrogen or unsubstituted alkyl.

In some embodiments, each of R ^16a and R ^16b is independently hydrogen.

In some embodiments, R ^16a and R ^16b are both hydrogen.

The ^R3 Group In some embodiments, ^R3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

In some embodiments, R ³ is substituted or unsubstituted alkyl.

In some embodiments, R ³ is substituted or unsubstituted C _1-6 alkyl.

In some embodiments, R ³ is C _1-3 alkyl optionally substituted with C _1-3 alkoxy.

In some embodiments, R ³ is methyl, ethyl, propyl, butyl, —CH ₂ OCH ₃ , or —CH ₂ OCH ₂ CH ₃ .

In some embodiments, R ₃ is methyl, ethyl, or n-propyl.

In some embodiments, ^R3 is methyl.

In some embodiments, R ³ is ethyl.

In some embodiments, R ³ is propyl.

The R ¹⁸ Group In some embodiments, R ¹⁸ is substituted or unsubstituted alkyl.

In some embodiments, R ¹⁸ is substituted or unsubstituted C _1-6 alkyl.

In some embodiments, R ¹⁸ is substituted C _1-6 alkyl.

In some embodiments, R ¹⁸ is unsubstituted C _1-6 alkyl.

In some embodiments, R ¹⁸ is methyl.

The R ¹⁹ Group In some embodiments, R ¹⁹ is hydrogen or substituted or unsubstituted C _1-6 alkyl.

In some embodiments, R ¹⁹ is unsubstituted C _1-3 alkyl.

In some embodiments, R ¹⁹ is hydrogen.

In some embodiments, R ¹⁹ is —CH ₃ .

In some embodiments, R ¹⁹ is hydrogen or methyl.

The Groups R ^{1 X} and/or R 1 ^Y In some embodiments, R 1 ^X is halo, —OH, —OR ^Q1 , or substituted or unsubstituted C _1-3 alkyl.

In some embodiments, R 2 ^X is —OH.

In some embodiments, R 1 ^Y is halo or unsubstituted alkyl.

In some embodiments, R 1 ^Y is halo or unsubstituted C _1-3 alkyl.

In some embodiments, R 1 ^Y is methyl, ethyl, or propyl.

In some embodiments, R 1 ^Y is methyl.

In some embodiments, R 1 ^X is —OH and R 1 ^Y is unsubstituted C _1-3 alkyl.

In some embodiments, R 1 ^X is —OH and R 1 ^Y is methyl.

In some embodiments, R ^{1 Y} and R 1 ^X , together with the intervening atoms, can form a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring.

In some embodiments, R 1 ^Y and R 1 ^X , together with the intervening atoms, can form a substituted or unsubstituted C _3-7 carbocyclic ring or a substituted or unsubstituted C _3-7 heterocyclic ring.

In some embodiments, R 1 ^Y and R 1 ^X , together with the intervening atoms, form a substituted or unsubstituted 4-membered carbocyclic ring.

In some embodiments, R 1 ^Y and R 1 ^X , together with the intervening atoms, form a substituted or unsubstituted 4-membered heterocyclic ring.

In some embodiments, the 4-membered heterocyclic ring contains a heteroatom selected from N, O, and S.

The Group R ^Q1 In some embodiments, R ^Q1 is unsubstituted C _1-6 alkyl.

In some embodiments, R ^Q1 is methyl.

The Group R ²² In some embodiments, R ²² , for each occurrence, is independently hydrogen, halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —N(R ^GA )C(═O)R ^GA , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ OR ^GA , —OS(═O) ₂ R ^GA , —S(═O) ₂ N(R ^GA ) ₂ , substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 carbosilyl, or substituted or unsubstituted C _3-6 heterosilyl; and R Each instance of ^GA is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 carbosilyl, substituted or unsubstituted C _3-6 heterosilyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R ²² , for each occurrence, is independently halogen, —CN, —OR ^GA , —N(R ^GA ) ₂ , substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 carbosilyl, and each instance of R ^GA is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or substituted or unsubstituted C _3-6 carbosilyl.

In some examples, R ²² , for each occurrence, is independently hydrogen, halogen, —CN, unsubstituted C _1-3 alkyl, substituted or unsubstituted C _3-6 heterosilyl, C _1-3 haloalkyl, or —OR ^GA , and each instance of R ^GA is independently hydrogen, substituted or unsubstituted C _1-3 alkyl.

In some embodiments, R ²² is located at the 4-position of the pyrazolyl.

In another embodiment, R ²² is located at the 3-position of the pyrazolyl.

In another embodiment, R ²² is located at the 5-position of the pyrazolyl.

In some embodiments, R ²² is —CN.

In another embodiment, R ²² is —CN located at the 4-position of the pyrazolyl.

integer n
In some embodiments, n is 1 or 2.

In some embodiments, n is 1, 2, or 3.

In some embodiments, n is 0 or 1.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, n is 3.

integer t
In some embodiments, t is 2. In some embodiments, t is 3.

integer r
In some embodiments, r is 2. In some embodiments, r is 3.

integer p
In some embodiments, p is 2. In some embodiments, p is 3.

integer s
In some embodiments, s is 2.

Integer q
In some embodiments, q is 2.

The R ⁵ Group In some embodiments, R ⁵ is methyl in the alpha or beta configuration.

In some embodiments, R ⁵ is methyl in the alpha configuration.

In some embodiments, R ⁵ is methyl in the beta configuration.

In some embodiments, R ⁵ is hydrogen in the alpha or beta configuration.

In some embodiments, R ⁵ is hydrogen in the alpha configuration.

In some embodiments, R ⁵ is hydrogen in the beta configuration.

In some embodiments, the compound of Formula I is a compound of Formula Ia:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula I is a compound of formula Ib:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of Formula I is a compound of Formula I-c or I-d:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula VIa or VIb is a compound of formula VIa-a or VIb-a:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula VIa or VIb is a compound of formula VIa-b or VIb-b:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula VIa or VIb is a compound of formula VIa-c, VIa-d, VIb-c, or VIb-d:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula VIa or VIb is a compound of formula VIa-e or VIb-e:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of Formula VII is a compound of Formula VII-a:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula VII is a compound of formula VII-b:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula VII is a compound of formula VII-c:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 below.

In one aspect, provided herein are pharmaceutically acceptable salts of compounds described herein (e.g., compounds of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X).

In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in the pharmaceutical composition in an effective amount. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

The compounds of the invention described herein, in certain embodiments, function as _GABA modulators, e.g., by acting on GABA _receptors in either a positive or negative manner. Such compounds are expected to have CNS activity as mediated by their ability to modulate _GABA receptors as regulators of CNS excitability.

Thus, in one aspect, provided herein is a method of modulating GABAA receptors in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of the claims herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In another aspect, a method of treating a CNS-related disorder in a subject in need thereof is provided, comprising administering to the subject an effective amount of a compound of the present invention. In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

Exemplary compounds of the present invention can be synthesized from the following known starting materials using methods known to those of skill in the art or certain references. In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X).

In alternative embodiments, the compounds described herein may also include one or more isotopic substitutions. For example, hydrogen may be ^2H (D or deuterium) or ^3H (T or tritium), carbon may be, for example, ^13C or ^14C , oxygen may be, for example, ^18O , nitrogen may be, for example, ^15N , etc. In other embodiments, a particular isotope (e.g., ^3H , ^13C , ^14C , ^18O , or ^15N ) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site in a compound.

Pharmaceutical Compositions In one aspect, provided herein are pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the invention is provided in the pharmaceutical composition in an effective amount. In certain embodiments, the compound of the invention is provided in a therapeutically effective amount.

In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient.

The pharmaceutical compositions provided herein may be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration.

Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered is typically determined by a physician taking into account the relevant circumstances, including the condition being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

When used to prevent the development of a CNS disorder, the compounds provided herein are typically administered at the dosage levels described above, under the advice and supervision of a physician, to subjects at risk of developing the condition. Subjects at risk of developing a particular condition generally include those with a family history of the condition or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, for example, for the life of the subject. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, for example, within the therapeutic window, for an extended period of time.

The pharmaceutical compositions of the present invention can be further delivered using various administration methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, e.g., to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic level of the active ingredient desired throughout the body; for example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., via an infusion) allows for a much faster delivery that quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, e.g., via an infusion, to provide for the maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still further embodiments, the pharmaceutical composition can be initially administered as a bolus dose, followed by a continuous infusion.

Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as single dosages for human subjects and other mammals, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect, in association with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions or pills, tablets, capsules, etc., in the case of solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that serve to form the desired dosage form.

For oral administration, a typical regimen is 1 to 5, particularly 2 to 4, and typically 3 oral doses per day. Using these dosing patterns, each dose provides about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses providing about 0.1 to about 10 mg/kg, particularly about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lower blood levels than those achieved using injection doses, and generally range from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

Injection dose levels range from about 0.1 mg/kg/hour to at least 20 mg/kg/hour, all for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is not expected to exceed about 5 g/day for a 40-80 kg human patient.

Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors, and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, or orange flavor.

Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As noted above, the active compound in such compositions is typically about 0.05-10% by weight, with the remainder being injectable excipients and the like.

Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as an ointment, the active ingredient is typically combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream having, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance dermal penetration of the active ingredient or stability of the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

The compounds provided herein may also be administered by a transdermal device. Thus, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

The above-described components of the orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, as well as processing techniques, are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

The compounds of the invention can also be administered in sustained-release forms or from sustained-release drug delivery systems. A description of representative sustained-release materials can be found in Remington's Pharmaceutical Sciences.

The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, and paratoluenesulfonate.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, e.g., a composition suitable for injection, such as intravenous (IV) administration.

Pharmaceutically acceptable excipients include any diluents or other liquid vehicles, dispersing or suspending aids, surfactants, isotonicity agents, preservatives, lubricants, etc., suitable for the particular dosage form desired, e.g., injection. General considerations in the formulation and/or manufacture of pharmaceutical compositions are described, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

For example, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated using suitable dispersing or wetting agents and suspending agents according to known techniques. Exemplary excipients that can be used include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of 6, 7, and 8 α-1,4-linked glucose units, respectively, and optionally contain one or more substituents on the linked sugar moieties, including, but not limited to, substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as CAPTISOL®. See, e.g., U.S. Patent No. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In more specific embodiments, the composition comprises hexapropyl-β-cyclodextrin (10-50% in water).

Injectable compositions can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered is typically determined by a physician, taking into account the relevant circumstances, including the condition being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

The compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as single dosages for human subjects and other mammals, each containing a predetermined quantity of active agent calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that serve to form the desired dosage form.

The compounds provided herein can be administered as the sole active agent or in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention with another pharmacologically active agent. Coadministration can proceed by any technique apparent to one of skill in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

While the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to animals of all kinds. Modifications of pharmaceutical compositions suitable for administration to humans to create compositions suitable for administration to a variety of animals are well understood, and those skilled in the art can design and/or perform such modifications with routine experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins, 2005.

In one aspect, a kit is provided that includes a composition (e.g., a solid composition) comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X.

Combination Therapy A compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) can be administered in combination with an additional agent or therapy. The subject to whom a compound disclosed herein is administered can have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. Combination therapy may be achieved by administering two or more agents, each of which may be formulated and administered separately, or by administering two or more agents in a single formulation. In some embodiments, combination therapy may be administered. Two or more drugs in a combination therapy can be administered simultaneously. In other embodiments, two or more drugs in a combination therapy are administered separately. For example, the administration of a first drug (or a combination of drugs) can be carried out minutes, hours, days, or weeks before the administration of a second drug (or a combination of drugs). Thus, two or more drugs can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases, even longer intervals are possible. In many cases, it is desirable that two or more drugs used in a combination therapy be present in a patient's body at the same time, but this does not have to be the case.

Combination therapy can also include two or more administrations of one or more of the drugs used in the combination, using different sequences of the constituent drugs. For example, when drug X and drug Y are used in combination, they can be administered one or more times sequentially in any combination, for example, in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc. Exemplary additional drugs are described below.

Selective serotonin reuptake inhibitors (SSRIs)
In some embodiments, a compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) may be administered in combination with one or more SSRIs. SSRIs include antidepressants that increase serotonin levels in the brain. Exemplary SSRIs include, but are not limited to, citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft).

Norepinephrine reuptake inhibitors (NERIs)
In some embodiments, a compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) is administered in combination with a NERI(s). Exemplary NERIs include, but are not limited to, atomoxetine (Strattera), reboxetine (Edronax, Vestra), bupropion (Wellbutrin, Zyban), duloxetine, desipramine (Norpramin), amedalin (UK-3540-1), daredalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), talopram (taslopram) (Lu 3-010), talsupram (Lu 5-005), tandamine (AY-23,946), and viloxazine (Vivalan).

In some embodiments, a compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) is administered in combination with an antipsychotic agent(s). Antipsychotic agents include D2 antagonists, which reduce dopaminergic neurotransmission in the dopamine pathway. Exemplary antipsychotics include, but are not limited to, asenapine (Saphris), aripiprazole (Abilify), cariprazine (Vrayar), clozapine (Clozaril), droperidol, fluperapine, mesoridazine, quetiapine hemi-fumarate, raclopride, spiperone, sulpiride, trimethobenzamide hydrochloride, trifluoroperazine dihydrochloride, lurasidone (Latuda), olanzapine (Zyprexa), quetiapine (Seroquel), zotepine, risperidone (Risperdal), ziprasidone (Geodon), mesothidazine, chlorpromazine hydrochloride, and haloperidol (Haldol).

Cannabinoids In some embodiments, a compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) may be administered in combination with a cannabinoid(s). Exemplary cannabinoids include, but are not limited to, cannabinoid (Epidiolex), tetrahydrocannabinolic acid, tetrahydrocannabinol, cannabinolic acid, cannabinol, cannabigerol, cannabichromene, tetrahydrocannabivarin, and cannabidivarin.

NMDA Receptor Antagonists In some embodiments, a compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) is administered in combination with an NMDA receptor antagonist(s). NMDA receptor antagonists are a class of drugs that inhibit the action of N-methyl-d-aspartate receptors. Exemplary NMDA antagonists include, but are not limited to, ketamine, esketamine, ketobemidone, ifendopril, 5,7-dichlorokynuric acid, licostinel, memantine, gabester, phencyclidine, dextromethorphan, remacemide, selfotel, tiletamine, dextropropoxyphene, aptiganel, dexanabinol, and amantadine. NMDA receptor antagonists also include opioids such as methadone, dextropropoxyphene, pethidine, levorphanol, tramadol, neramexane, and ketobemidone.

GABA Receptor Agonists In some embodiments, a compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) is administered in combination with one or more GABA receptor agonists. GABA receptor agonists are a class of drugs that are agonists for one or more GABA receptors. Exemplary GABA receptor agonists include clobazam, topiramate, muscimol, progabide, riluzole, baclofen, gabapentin, vigabatrin, valproic acid, tiagabine, lamotrigine, pregabalin, phenyloin, carbamazepine, thiopental, thiamylal, pentobarbital, secobarbital, hexobarbital, butobarbital, amobarbital, barbital, mephobarbital, phenobarbital, primidone, midazolam, triazolam, lometazepam, flutazolam, nitrazepam, fluritrazepam, nimetazepam, diazepam, medazepam, oxazolam, prazepam, tofizoam, rilmazafone, lorazepam, temazepam, oxazepam, fludiazepam, chlordiazepine, and the like. oxide, cloxazolam, flutoprazepam, alprazolam, estazolam, bromazepam, flurazepam, clorazepate potassium, haloxazolam, ethyl loflazepate, quazepam, clonazepam, mexazolam, etizolam, brotizolam, clotiazepam, propofol, fospropofol, zolpidem, zopiclone, eszopiclone, muscimol, TFQP/gaboxadol, isoguvacine, kodiamine, GABA, homotaurine, homohypotaurine, trans-aminocyclopentane-3-carboxylic acid, trans-amino-4-crotonic acid, b-guanidinopropionic acid, homo-b-proline, isonipecotic acid, 3-((aminoiminomethyl)thio)-2-propenoic acid (ZAP) Examples of suitable amines include, but are not limited to, imidazole acetic acid, imidazole acetic acid, and piperidine-4-sulfonic acid (P4S).

Cholinesterase Inhibitors In some embodiments, a compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) is administered in combination with a cholinesterase inhibitor(s). Generally, cholinergics are compounds that mimic the actions of acetylcholine and/or butylcholine. Cholinesterase inhibitors are a class of drugs that prevent the breakdown of acetylcholine. Exemplary cholinesterase inhibitors include, but are not limited to, donepidil (Aricept), tacrine (Cognex), rivastigmine (Exelon, Exelon Patch), galantamine (Razadyne, Reminyl), memantine/donepezil (Namzaric), ambenonium (Mytelase), neostigmine (Bloxiverz), pyridostigmine (Mestinon Timespan, Regonol), and galantamine (Razadyne).

The present disclosure also contemplates, inter alia, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) to a subject who has previously been administered an agent selected from the group consisting of a bronchial muscle/airway relaxant, an antiviral agent, oxygen, an antibody, and an antibacterial agent. In some embodiments, the additional agent is administered to the subject prior to administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof), and the additional agent is selected from the group consisting of a bronchial muscle/airway relaxant, an antiviral agent, oxygen, an antibody, and an antibacterial agent. In some embodiments, a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) is co-administered to a subject with an agent selected from a bronchial muscle/airway relaxant, an antiviral agent, oxygen, and an antibacterial agent.

Methods of Use and Treatment In certain embodiments, the compounds described herein, e.g., compounds of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, are used to treat a CNS-related disorder (e.g., a sleep disorder, a mood disorder (e.g., depression, schizophrenia spectrum disorder, seizure disorder, epileptogenesis, memory and/or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and/or withdrawal syndrome, or tinnitus) in a subject (e.g., Exemplary CNS conditions associated with GABA modulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), dysthymic disorders (e.g., mild depression), bipolar disorder (e.g., I and/or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), and the like. ), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorder (e.g., schizophrenia, schizoaffective disorder)], convulsive disorder (e.g., epilepsy (e.g., status epilepticus (SE), seizures)], memory impairment and/or cognitive impairment (e.g., attention disorder (e.g., attention deficit hyperactivity disorder (ADHD), dementia (e.g., Alzheimer's disease, dementia with Lewy bodies, vascular dementia), movement disorder (e.g., Huntington's disease, Parkinson's disease), personality disorder (e.g., antisocial personality disorder, Symptoms of tinnitus include, but are not limited to, neurological disorders, autism spectrum disorders (ASDs) [e.g., autism, synaptopathy, monogenic causes of autism such as Rett Syndrome, Fragile X Syndrome, Angelman Syndrome, etc.], pain [e.g., neuropathic pain, injury-related pain syndromes, acute pain, chronic pain], traumatic brain injury (TBI), vascular disease [e.g., stroke, ischemia, vascular malformation], substance abuse disorders and/or withdrawal syndromes [e.g., opiate, cocaine, and/or alcohol addiction], and tinnitus.

In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and/or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder.

In certain aspects, methods are provided for alleviating or preventing seizure activity in a subject, comprising administering an effective amount of a compound of the present invention to a subject in need of such treatment. In some embodiments, the method alleviates or prevents epileptogenesis.

In yet another aspect, combinations of compounds of the present invention with another pharmacologically active agent are provided. The compounds provided herein can be administered as the sole active agent or in combination with other agents. Coadministration can proceed by any technique apparent to one of skill in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

In another aspect, a method for treating or preventing brain excitability in a subject susceptible to or suffering from a condition associated with brain excitability is provided, comprising administering to the subject an effective amount of a compound of the present invention.

In yet another aspect, there is provided a method for treating or preventing stress or anxiety in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention or a composition thereof.

In yet another aspect, there is provided a method for alleviating or preventing insomnia in a subject, comprising administering an effective amount of a compound of the present invention or a composition thereof to a subject in need of such treatment.

In yet another aspect, a method is provided for inducing sleep and substantially maintaining levels of REM sleep found in normal sleep without the induction of substantial rebound insomnia, comprising administering an effective amount of a compound of the present invention.

In yet another aspect, there is provided a method for alleviating or preventing premenstrual syndrome (PMS) or postpartum depression (PND) in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention.

In yet another aspect, methods are provided for treating or preventing a mood disorder in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention. In certain embodiments, the mood disorder is depression.

In yet another aspect, methods are provided for treating cognitive enhancement or memory impairment by administering a therapeutically effective amount of a compound of the present invention to a subject. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

In yet another aspect, there is provided a method for treating an attention disorder by administering a therapeutically effective amount of a compound of the present invention to a subject. In certain embodiments, the attention disorder is ADHD.

Inflammation of the central nervous system (CNS) (neuroinflammation) is recognized as a hallmark of all neurological disorders. Primary inflammatory neurological disorders include multiple sclerosis (characterized by an immune-mediated response to myelin proteins) and meningoencephalitis (in which an infectious agent triggers an inflammatory response). Additional scientific evidence suggests a potential role for inflammatory mechanisms in other neurological conditions, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, and traumatic brain injury. In one embodiment, compounds of the present invention are useful for treating neuroinflammation. In another embodiment, compounds of the present invention are useful for treating inflammation in neurological conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, and traumatic brain injury.

In certain embodiments, the compound is administered chronically to the subject. In certain embodiments, the compound is administered orally, subcutaneously, intramuscularly, or intravenously to the subject.

Neuroendocrine Disorders and Dysfunctions Provided herein are methods that can be used to treat neuroendocrine disorders and dysfunctions. As used herein, "neuroendocrine disorder" or "neuroendocrine dysfunction" refers to various conditions caused by an imbalance in the body's hormone production, which is directly related to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. Because the hypothalamus and pituitary gland are two areas of the brain that regulate hormone production, damage to the hypothalamus or pituitary gland, for example, due to traumatic brain injury, can affect hormone production and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women's health disorder or condition (e.g., a women's health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction associated with a women's health disorder or condition is polycystic ovary syndrome.

Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, reproductive symptoms, and somatic symptoms, including, but not limited to, fatigue, poor memory, anxiety, depression, weight gain or loss, emotional sustainability, lack of concentration, decreased attention span, decreased lipids, infertility, amenorrhea, decreased muscle mass, increased abdominal body fat, low blood pressure, slow heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

Neurodegenerative Diseases and Disorders The methods described herein can be used to treat neurodegenerative diseases and disorders. The term "neurodegenerative disease" includes diseases and disorders associated with the progressive loss of neuronal structure or function, or the death of neurons. Neurodegenerative diseases and disorders include Alzheimer's disease (including associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injury; ataxia and seizures (including the treatment and prevention of seizures caused by schizoaffective disorder or drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neurospinous syndrome (MLS); closed head injury; coma; contusion (e.g., spinal cord injury and head injury); dementia, including multi-infarct dementia and senile dementia; disorders of consciousness; and Down's syndrome. Drug-induced or medication-induced parkinsonism (neuroleptic-induced acute akathisia, acute dystonia, parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or drug-induced postural tremor); epilepsy; fragile X syndrome; Tourette's syndrome; head trauma; hearing impairment and hearing loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including akinesia and akinesia (rigid) syndrome (basal ganglia calcification, corticobasal degeneration, multiple system atrophy, parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism) muscle spasms and disorders related to muscle spasms or weakness (including chorea such as benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham chorea, and symptomatic chorea), dyskinesias (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cycloclonus), tremors (such as rest tremor, postural tremor, and intention tremor) and dystonias (axial dystonia, dystonic writer's cramp, hemiplegic dystonia) Neurodegenerative diseases include, but are not limited to, neurotoxic damage following stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral thrombosis, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and cardiac arrest. Neurodegenerative diseases also include, but are not limited to, neurotoxic damage following stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and cardiac arrest. Methods for treating or preventing neurodegenerative diseases also include treating or preventing the loss of nerve cell function that is characteristic of neurodegenerative diseases.

Also provided herein are methods for treating mood disorders, such as clinical depression, postnatal or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, dual depression, depressive personality disorder, recurrent brief depression, mild depressive disorder, bipolar or manic-depressive disorder, depression caused by a chronic medical condition, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic benefit to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression may have trouble sleeping, lose weight, and be generally agitated and irritable. Clinical depression affects an individual's feelings, thoughts, and behaviors and can lead to a variety of emotional and physical problems. People with clinical depression may have trouble performing everyday activities and feel that life is not worth living.

Perinatal depression refers to depression during pregnancy. Symptoms may include irritability, crying, restlessness, sleep disturbances, extreme fatigue (emotional and/or physical), changes in appetite, difficulty concentrating, increased anxiety and/or worry, feelings of disconnection from the baby and/or fetus, and loss of interest in previously enjoyed activities.

Postnatal depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that affects women after giving birth. Symptoms can include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant depression (e.g., a treatment-resistant depression described herein). In some embodiments, the PND is a treatment-refractory depression (e.g., a treatment-refractory depression described herein).

In some embodiments, a subject with PND also experienced depression, or symptoms of depression, during pregnancy. This depression is referred to herein as perinatal depression. In certain embodiments, a subject who experiences perinatal depression is at increased risk of experiencing PND.

Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and aggressiveness, marked weight gain, or increased appetite. Patients with AD may also have significant social impairments as a result of excessive sleep or sleepiness (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to perceived social rejection.

Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), failure to respond to pleasurable stimuli, depressed mood that predominates over sadness or loss, excessive weight loss, or excessive guilt.

Psychotic major depression (PMD) or psychotic depression refers to major depressive episodes, particularly of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. The individual may become silent and stuporous, immobile, or exhibit aimless or bizarre movements.

Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes occurring in the fall or winter.

Dysthymia refers to a condition related to unipolar depression that manifests with the same physical and cognitive problems. These tend to be less severe and last longer (e.g., at least 2 years).

Dual depression refers to a period of significant depressed mood (dysthymia) lasting at least two years, interrupted by periods of major depression.

Depressive personality disorder (DPD) refers to a personality disorder with depressive features.

Recurrent brief depression (RBD) refers to a condition in which an individual experiences depressive episodes about once a month, each lasting less than two weeks, or typically less than two to three days.

Mild depressive disorder or mild depression refers to depression in which at least two symptoms are present for two weeks.

Bipolar or manic-depressive disorder causes extreme mood swings, including emotional highs (mania or hypomania) and lows (depression). During manic periods, the individual may feel or behave unusually happy, energetic, or irritable. They often make ill-considered decisions with little consideration for the consequences. The need for sleep is usually reduced. During depressive periods, individuals may cry, make less eye contact with others, and have a negative outlook on life. The risk of suicide for people with the disorder is high, exceeding 6% over a 20-year period, and self-harm occurs in 30-40% of cases. Other mental health problems, such as anxiety disorders and substance use disorders, are commonly associated with bipolar disorder.

Depression caused by a chronic medical condition refers to depression caused by a chronic medical condition such as cancer or chronic pain, chemotherapy, or chronic stress.

Treatment-resistant depression refers to a condition in which an individual has received treatment for depression but their symptoms do not improve. For example, antidepressants or physiological counseling (psychotherapy) do not alleviate depressive symptoms in individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve but then return. Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and/or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and/or transcranial magnetic stimulation).

Postoperative depression refers to feelings of depression following a surgical procedure (e.g., as a result of having to face one's own mortality). For example, an individual may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in hobbies and activities that they normally enjoy, or persistent feelings of worthlessness or hopelessness.

A mood disorder associated with a women's health condition or disorder refers to a mood disorder (e.g., depression) associated with (e.g., caused by) a women's health condition or disorder (e.g., those described herein).

Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to attempt suicide. Suicidal ideation involves thoughts or an abnormal preoccupation with suicide. Suicidal ideation can range from, for example, momentary thoughts to extensive thinking, detailed plans, role-playing, and aborted attempts. Symptoms may include talking about suicide, obtaining the means to attempt it, withdrawing from social contacts, becoming preoccupied with death, feeling trapped or hopeless in a situation, increasing alcohol or drug use, doing something risky or self-destructive, and saying goodbye to people as if they will never see each other again.

Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, feelings of worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, impaired mobility, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, low self-esteem, absence of positive thoughts or plans, excessive sleeping, overeating, loss of appetite, insomnia, self-harm, thoughts of suicide, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. Depression symptoms, and their relief, can be confirmed by a doctor or psychologist (e.g., by mental status examination).

In some embodiments, the method includes monitoring the subject using a known depression scale, such as the Hamilton Depression (HAM-D) scale, the Clinical Global Impression-Improvement scale (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by a reduction in the Hamilton Depression (HAM-D) total score exhibited by the subject. The reduction in the HAM-D total score can occur within 4, 3, 2, or 1 day, or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. The therapeutic effect can be assessed over a specified treatment period. For example, therapeutic efficacy can be determined by a decrease from baseline in HAM-D total score after administration of a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more; or 1 day, 2 days, 14 days, 21 days, or 28 days; or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months, or 10 months; or 1 year, 2 years, or lifetime).

In some embodiments, the subject has a mild depressive disorder, e.g., a mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., a moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., a severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., a very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., before treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is between 14 and 18, inclusive. In some embodiments, the subject's baseline HAM-D total score is between 19 and 22, inclusive. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is 23 or greater. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the subject's HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is less than 10, 7, 5, or 3. In some embodiments, the reduction in HAM-D total score is from a baseline score of about 20-30 (e.g., 22-28, 23-27, 24-27, 25-27, 26-27) to a HAM-D total score of about 0-10 (e.g., less than 10; 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8) after treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X. In some embodiments, the reduction in HAM-D total score from baseline after treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100-fold. In some embodiments, the reduction in HAM-D total score from baseline after treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured as a reduction in the HAM-D total score after treatment (e.g., 12, 24, 48 hours, or 24, 48, 72, 96 hours or more, or 1 day, 2 days, 14 days or more after administration) with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, compared to the baseline HAM-D total score, of at least 10, 15, or 20 points.

In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g., as measured by a reduction in the Hamilton Depression Score (HAM-D)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant reduction in the HAM-D total score) within the first or second day of treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X. In some embodiments, methods for treating depressive disorders, e.g., major depressive disorder, provide a therapeutic benefit (e.g., as determined by a statistically significant reduction in HAM-D total score) within 14 days of initiating treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X. In some embodiments, methods for treating depressive disorders, e.g., major depressive disorder, provide a therapeutic benefit (e.g., as determined by a statistically significant reduction in HAM-D total score) within 21 days of initiating treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant reduction in HAM-D total score) within 28 days of initiating treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X. In some embodiments, the therapeutic effect is a reduction from baseline in HAM-D total score following treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X (e.g., 14 days of once-daily treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X). In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is at least 24. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is at least 18. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is between 14 and 18, inclusive. In some embodiments, the reduction in HAM-D total score after treating a subject with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, compared to the baseline HAM-D total score is at least 10. In some embodiments, the reduction in HAM-D total score after treating a subject with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, compared to the baseline HAM-D total score is at least 15 (e.g., at least 17). In some embodiments, the HAM-D total score associated with treating a subject with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is a number in the range of 6 to 8 or less. In some embodiments, treating a subject with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is associated with a HAM-D total score of 7 or less.

In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Clinical Global Impression (CGI) scale) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a reduction in the CGI score from baseline at the end of the treatment period (e.g., 14 days after administration).

In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a reduction in the MADRS score from baseline at the end of the treatment period (e.g., 14 days after administration).

The effectiveness of treatment for major depressive disorder can be determined by a reduction in the subject's Montgomery-Asberg Depression Rating Scale (MADRS) score. For example, the MADRS score may be reduced within 4, 3, 2, or 1 day, or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (addressing apparent sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, loss of sensation, pessimistic thoughts, and suicidal ideation) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders.

In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Generalized Anxiety Disorder 7-item scale (GAD-7)) within 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours.

Anxiety Disorders Provided herein are methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, and post-traumatic stress disorder). Anxiety disorder is an umbrella term that covers several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

Generalized anxiety disorder is a common chronic illness characterized by long-term anxiety that is not focused on any one object or situation. People suffering from generalized anxiety experience persistent, nonspecific fear and worry and become excessively concerned with everyday events. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

In panic disorder, individuals experience brief attacks of intense fear and anxiety, often characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks are defined by the APA as a sudden onset of fear or discomfort that peaks in less than 10 minutes, but can last for several hours and may be triggered by stress, fear, or exercise. However, the specific cause is not always clear. In addition to recurring unexpected panic attacks, a diagnosis of panic disorder also requires the presence of chronic consequences, either worry about the potential impact of the attacks, ongoing fear of future attacks, or significant changes in behavior related to the attacks. Thus, individuals with panic disorder experience symptoms outside of specific panic episodes. Often, normal changes in heart rate are noticed by panic sufferers, leading them to believe something is wrong with their heart or that another panic attack is imminent. In some cases, heightened awareness of bodily functions (hypervigilance) occurs during panic attacks, and the perceived physiological changes are interpreted as potentially life-threatening illness (i.e., extreme hypochondria).

Obsessive-compulsive disorder is a type of anxiety disorder characterized primarily by recurrent obsessions (distressing, persistent, intrusive thoughts or images) and compulsions (urges to perform certain actions or rituals). OCD thought patterns have sometimes been likened to superstition, in that they involve belief in nonexistent causal relationships. Often, this process is not entirely logical; for example, a compulsion to walk in a particular pattern may be used to alleviate obsessive thoughts of imminent harm. Often, compulsions are simply completely inexplicable urges to complete tension-induced rituals. In a minority of cases, patients with OCD can experience only obsessions without any apparent compulsions, and a much smaller number experience only compulsions.

The single largest category of anxiety disorders is that of phobias, which includes all cases in which fear and anxiety are triggered by a specific stimulus or situation. Patients typically anticipate frightening consequences from encountering the feared object (anything from an animal to a place to a bodily fluid).

Post-traumatic stress disorder (PTSD) is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can result from extreme situations such as combat, rape, hostage situations, or even serious accidents. It can also result from prolonged (chronic) exposure to intense stressors, such as soldiers who endure individual battles but are unable to cope with sustained combat. Common symptoms include flashbacks, avoidance behaviors, and depression.

Women's Health Disorders Provided herein are methods for treating conditions or disorders related to women's health, including, but not limited to, gynecological health and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), fertility issues (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, and issues related to women's overall health and wellness (e.g., menopause).

Gynecological health and disorders affecting women include menstruation and menstrual irregularities, urinary tract health, including urinary incontinence and pelvic floor disorders, and disorders such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvar disorders.

Premenstrual syndrome (PMS) refers to the physical and emotional symptoms that occur one to two weeks before a woman's period. Symptoms vary but can include bleeding, mood swings, breast tenderness, food cravings, fatigue, irritability, acne, and depression.

Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Symptoms of PMDD are similar to PMS but are more severe and can interfere with work, social activities, and relationships. PMDD symptoms include mood swings, depressed mood or feelings of hopelessness, noticeable anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, appetite changes, feeling out of control or overwhelming, sleep disturbances, and physical problems (e.g., bloating, breast tenderness, swelling, headaches, joint or muscle pain).

Pregnancy issues include preconception and prenatal care, pregnancy loss (miscarriage and stillbirth), preterm labor and birth, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

A miscarriage is a pregnancy that ends naturally within the first 20 weeks of pregnancy.

Abortion refers to the intentional termination of a pregnancy, which can occur during the first 28 weeks of pregnancy.

Infertility and related conditions include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian failure.

Polycystic ovary syndrome (PCOS) refers to an endocrine system disorder in women of reproductive age. PCOS is a group of symptoms caused by elevated levels of male hormones in women. Most women with PCOS develop many small cysts on their ovaries. Symptoms of PCOS include irregular or absent menstrual periods, heavy menstrual periods, excess body and facial hair, acne, pelvic pain, difficulty conceiving, and patches of thick, dark, velvety skin. PCOS may be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

Other diseases and conditions that only affect women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

Issues related to women's overall health and wellness include violence against women, women with disabilities and their unique challenges, osteoporosis and bone health, and menopause.

Menopause refers to the end of a woman's menstrual cycle, occurring 12 months after her last menstrual period. Menopause typically occurs in women in their 40s or 50s. Physical symptoms, such as hot flashes and emotional symptoms of menopause, can disrupt sleep, reduce energy, or cause anxiety or feelings of sadness or loss. Menopause includes natural menopause and surgical menopause, a type of induced menopause resulting from events such as surgery (e.g., hysterectomy, oophorectomy, cancer). It is induced when the ovaries are severely damaged, for example, by radiation, chemotherapy, or other drugs.

Epilepsy A compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable composition thereof, can be used in the methods described herein, e.g., in the treatment of a disorder described herein, such as epilepsy, status epilepticus, or seizures.

Epilepsy is a brain disorder characterized by recurrent seizures over time. Types of epilepsy include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures during awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy and frontal lobe epilepsy, and benign focal epilepsy of childhood.

Epileptogenesis The compounds and methods described herein can be used to treat or prevent epileptogenesis, a stepwise process by which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptogenesis results from neuronal damage caused by an earlier seizure (e.g., status epilepticus).

Status epilepticus (SE)
Status epilepticus (SE) includes, for example, convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, and very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptic-like discharges, and periodic lateralized epileptic-like discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus episodes and can include early status epilepticus, established status epilepticus, refractory status epilepticus, and very refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by persistent status epilepticus episodes despite treatment with first-line therapy, and second-line therapy is administered. Refractory status epilepticus is characterized by persistent seizures of status epilepticus despite treatment with first-line and second-line therapies, typically with general anesthetics. Super-refractory status epilepticus is characterized by persistent seizures of status epilepticus despite treatment with first-line and second-line therapies and general anesthetics for 24 hours or more.

Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus, generalized non-convulsive status epilepticus, e.g., delayed absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

A compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, can also be administered as a prophylactic agent prior to the onset of a seizure to a subject with a CNS disorder, e.g., traumatic brain injury; status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges.

Seizures Seizures are physical findings or behavioral changes that occur after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A convulsion is a rapid and uncontrollable shaking of a person's body. During a convulsion, a person's muscles repeatedly contract and relax.

Based on the type of behavior and brain activity, seizures are classified into two broad categories: generalized and partial (also called focal or localized). Classifying the type of seizure helps doctors diagnose whether a patient has epilepsy.

Generalized seizures are caused by electrical impulses from the entire brain, while partial seizures are caused (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain that generates the seizure is sometimes called the focus.

There are six types of generalized seizures. The most common, dramatic, and therefore best known is the generalized convulsion, also called a grand mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. Loss of consciousness is followed by 30-60 seconds of whole-body rigidity (called the "tonic" phase of the seizure), followed by 30-60 seconds of violent jerking (the "clonic" phase), after which the patient enters a deep sleep (the "post-ictal" or post-ictal phase). Injuries and accidents such as tongue biting and urinary incontinence can occur during a grand mal seizure.

Absence seizures cause a brief loss of consciousness (only a few seconds) with few or no symptoms. Affected people, most often children, typically stop their activities and stare blankly. These seizures begin and end suddenly and can occur several times a day. Affected people are usually unaware they are having a seizure, but may be aware that they are "losing time."

Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients may describe the jerks as brief electric shocks. When severe, these seizures may cause objects to be dropped or thrown involuntarily.

Clonal seizures are repetitive, rhythmic jerks that involve both sides of the body simultaneously.

Tonic seizures are characterized by muscle stiffness.

Atonic seizures consist of a sudden, generalized loss of muscle rigidity, especially in the arms and legs, often resulting in a fall.

Seizures described herein may include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; discontinuous seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; affective seizures; focal seizures; gibberish; generalized seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonic seizures; multiple seizures; neonatal-onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; petit mal seizures, Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberculous sclerosis complex, Rett syndrome, or PCDH19 epilepsy of girls.

Movement Disorders Also described herein are methods for treating movement disorders.As used herein, "movement disorder" refers to various diseases and disorders associated with hyperactivity and related abnormalities in muscle control.Exemplary movement disorders include, but are not limited to, Parkinson's disease and parkinsonism (particularly defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tic and Tourette's syndrome, restless legs syndrome, stiff person syndrome, and gait disorders.

Tremor The methods described herein can be used to treat tremor, for example, a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X can be used to treat cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiologic tremor, psychogenic tremor, or rubral tremor. Tremors include genetic, degenerative, and idiopathic disorders such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid and parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Lucy-Lewy, diabetes, and complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced disorders (narcolepsy, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychiatric disorders. Clinical tremor can be classified as physiologic tremor, intensified physiologic tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task- and postural-specific tremor), dystonic tremor, Parkinsonian tremor, cerebellar tremor, Holmes tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor.

Tremor is the involuntary, sometimes rhythmic contraction and relaxation of muscles, which may involve vibration or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after intentional movement. Cerebellar tremor can be caused by lesions or damage to the cerebellum, for example, due to tumors, stroke, or disease (e.g., multiple sclerosis, inherited degenerative disorders).

Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting, repetitive movements, and/or painful and abnormal postures or positions. Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and can often be relieved by complete rest.

Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive or progress slowly, starting on one side of the body but affecting both sides within three years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. Tremor frequency may decrease with age, but severity may increase. Heightened emotions, stress, fever, physical fatigue, or hypoglycemia may trigger tremor and/or increase its severity. Symptoms generally progress over time and may be both noticeable and persistent after onset.

Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions in the legs and trunk that occur immediately after standing. Cramps can be felt in the thighs and legs, and patients may sway uncontrollably when asked to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

Parkinsonian tremor is caused by damage to structures in the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson's disease and is typically seen as "pill-making" movements of the hands, and can also affect the jaw, lips, legs, and trunk. Onset of Parkinsonian tremor typically begins after age 60. Movements can begin in one limb or one side of the body and progress to involve the other side.

Physiologic tremor can occur in normal individuals and is not clinically significant. It can be seen in all voluntary muscle groups. Physiologic tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including an overactive thyroid gland and hypoglycemia. Tremor classically has a frequency of approximately 10 Hz.

Psychogenic or hysterical tremor can occur at rest or during bodily movement or motor activity. Patients with psychogenic tremor may have conversion disorder or another psychiatric disorder.

Red tremor is characterized by a coarse, slow tremor that can be present at rest, during posture, and at will. The tremor is associated with conditions affecting the red nucleus of the midbrain, a classic abnormal stroke.

Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle stiffness, tremors, and changes in speech and gait. Parkinsonism is characterized by tremors, bradycardia, rigidity, and postural instability. Parkinsonism shares symptoms with Parkinson's disease, but is a group of conditions rather than a progressive neurodegenerative disease.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal, often repetitive movements or postures. Dystonic movements can be patterned, twisting, or tremor-like. Dystonia is often initiated or exacerbated by voluntary actions and is associated with overflow muscle activation.

Chorea is a neurological disorder characterized by spasmodic, involuntary movements that typically affect the shoulders, hips, and face. Huntington's disease is a genetic disorder that weakens nerve cells in the brain. Symptoms include uncontrollable movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, speaking, and swallowing.

Ataxia refers to the complete loss of control over bodily movements and can affect fingers, hands, arms, legs, torso, speech, and eye movements.

Myoclonus and startle are responses to sudden, unexpected stimuli, which can be acoustic, tactile, visual, or vestibular.

Tics are involuntary movements, usually of sudden onset; they are brief, repetitive, but not rhythmic; they typically mimic normal behavior and often occur against a background of normal activity. Tics can be classified as motor or vocal; motor tics are associated with movement, while vocal tics are associated with sound. Tics are characterized as simple or complex; for example, simple motor tics involve only a few muscles restricted to a specific body part. Tourette's syndrome is a childhood-onset genetic neuropsychiatric disorder characterized by multiple motor tics and at least one vocal tic.

Restless legs syndrome is a neurosensory-motor disorder characterized by an overwhelming urge to move the legs while at rest.

Stiff-person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle rigidity, usually involving the hips and legs. A stiff-legged gait with exaggerated lumbar hyperlordosis is the typical outcome. Characteristic abnormalities in EMG recordings, associated with continuous motor unit activity of the paraaxial muscles, are typically observed. Variants include "stiff limb syndrome," which produces focal stiffness typically affecting the distal legs and feet.

Gait disorders refer to abnormalities in the manner or style of walking resulting from neuromuscular, arthritic, or other physical changes. Gaits are classified according to the system responsible for the abnormal movement, including hemiplegic, diplegic, neuropathic, myopathic, parkinsonian, choreiform, ataxic, and sensory gait.

Anesthesia/Sedation Anesthesia is a pharmacologically induced, reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects can be obtained from a single drug that alone provides the correct combination of effects, or occasionally with a combination of drugs (e.g., hypnotics, sedatives, paralysis, analgesics) to achieve a very specific combination of results. Anesthesia allows patients to undergo surgery and other procedures without the pain they would otherwise experience.

Sedation is the reduction of irritability or excitability, generally through the administration of pharmacological agents, to facilitate a medical or diagnostic procedure.

Sedation and analgesia encompass a range of states of consciousness from minimal sedation (anxiolysis) to general anesthesia.

Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state in which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular function are usually unaffected.

Moderate sedation/analgesia (conscious sedation) is a drug-induced decrease in consciousness in which the patient responds purposefully to verbal commands, either alone or with light tactile stimulation. No intervention is usually required to maintain a patent airway. Spontaneous ventilation is typically adequate. Cardiovascular function is usually preserved.

Deep sedation/analgesia is a drug-induced decrease in consciousness during which the patient is not easily aroused but responds purposefully after repeated or painful stimuli (rather than reflex withdrawal from painful stimuli). Independent ventilatory function may be impaired, and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually preserved.

General anesthesia is a drug-induced loss of consciousness during which the patient is not aroused, even by painful stimuli. The ability to maintain independent ventilatory function is often impaired, and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to decreased spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.

Sedation in the intensive care unit (ICU) allows patients to become less aware of their environment and less responsive to external stimuli. This can play a role in the care of critically ill patients and encompasses a wide range of symptom control that may vary between patients and between individuals throughout their illness course. Heavy sedation in critical care is often used in conjunction with neuromuscular blocking agents to facilitate endotracheal tube tolerance and ventilator synchronization.

In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced and maintained in the ICU for an extended period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedation may have a long-term effect. Sedation in the ICU may have a short elimination half-life.

Procedural sedation and analgesia, also known as conscious sedation, is a technique in which sedatives or dissociative agents are administered with or without analgesics to induce a state that allows the subject to tolerate an unpleasant procedure while maintaining cardiopulmonary function.

Also described herein is a method for ameliorating one or more symptoms of a respiratory disorder in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof).

In one aspect, provided herein is a method of treating a subject wherein the subject exhibits one or more symptoms of and/or has been diagnosed with a respiratory disorder, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof).

In some embodiments, the present disclosure contemplates a method of treating a subject having a respiratory disease, comprising administering to the subject a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof).

In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory disease may result in a reduction in the severity of one or more symptoms of the respiratory disease, or a delay or slowing of the progression of one or more symptoms of the respiratory disease.

In some embodiments, the subject with a respiratory disorder has been or is being treated with mechanical ventilation or oxygen. In some embodiments, the subject with a respiratory disorder has been or is being treated with mechanical ventilation.

In some embodiments, a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) is administered to a subject who is being treated or has been treated with mechanical ventilation. In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) is continued throughout treatment of the subject with mechanical ventilation. In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) continues after the subject has ceased treatment with mechanical ventilation.

In some embodiments, a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) is administered to a subject undergoing or who has undergone treatment with a sedative agent. In some embodiments, the sedative agent is propofol or a benzodiazepine.

In some embodiments, the disclosure includes administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) to a subject in need thereof in an amount sufficient to increase blood oxygen saturation. In some embodiments, blood oxygen saturation is measured using pulse oximetry.

In some embodiments, the present disclosure contemplates a method of treating a cytokine storm in a patient. In some embodiments, the method comprises administering to a patient a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof). In some embodiments, a symptom of a cytokine storm is pulmonary inflammation. In some embodiments, a patient experiencing a cytokine storm has acute respiratory distress syndrome (ARDS).

Respiratory Disorders In some embodiments, a subject with a respiratory disorder suffers from respiratory distress. In some embodiments, the respiratory distress comprises acute respiratory distress.

In some embodiments, a subject with a respiratory disorder may exhibit one or more symptoms selected from the group consisting of airway hyperresponsiveness, inflammation of lung tissue, pulmonary hypersensitivity, and inflammation-associated lung pain.

In some embodiments, a subject with a respiratory disease may exhibit inflammation of lung tissue. In some embodiments, the inflammation of lung tissue is bronchitis or bronchiectasis. In some embodiments, the inflammation of lung tissue is pneumonia. In some embodiments, the pneumonia is ventilator-associated pneumonia or hospital-acquired pneumonia. In some embodiments, the pneumonia is ventilator-associated pneumonia.

In some embodiments, administration of a compound or pharmaceutical composition described herein to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of respiratory distress in the subject with the respiratory disease, or delays or slows the progression of respiratory distress in the subject with the respiratory disease.

In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of airway hyperresponsiveness in the subject with a coronavirus-associated disease, or delays or slows the progression of airway hyperresponsiveness in the subject with a respiratory disease.

In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of inflammation of lung tissue in the subject with the respiratory disease, or delays or slows the progression of inflammation of lung tissue in the subject with the respiratory disease. In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of pneumonia in the subject with the respiratory disease, or delays or slows the progression of pneumonia in the subject with the respiratory disease.

In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of pulmonary hypersensitivity in the subject with the respiratory disease, or delays or slows the progression of pulmonary hypersensitivity in the subject with the respiratory disease.

In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of inflammation-associated pulmonary pain in the subject with the respiratory disease, or delays or slows the progression of inflammation-associated pulmonary pain in the subject with the respiratory disease.

In some embodiments, the subject with a respiratory disease is receiving or has received treatment for an infection, fibrosis, a fibrotic episode, chronic obstructive pulmonary disease, sarcoidosis (or pulmonary sarcoidosis), or asthma/asthma-related inflammation.

In some embodiments, the subject exhibits symptoms of and/or has been diagnosed with asthma. In some embodiments, the subject is experiencing or has experienced an asthma attack.

In some embodiments, the subject is undergoing or has undergone treatment for fibrosis or a fibrotic episode. In some embodiments, the fibrosis is cystic fibrosis.

In some embodiments, the respiratory disease is cystic fibrosis, asthma, smoke-induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, congenital bilateral absence of the vas deferens (CBAVD), mild lung disease, pulmonary sarcoidosis, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation fibrosis deficiency (e.g., protein C deficiency), hereditary type 1 vasoconstrictor syndrome (VAS), or pulmonary edema. tumors, lipid processing defects (e.g., familial hypercholesterolemia), type 1 chylomicronemia, abetalipoproteinemia, hemolytic storage diseases (e.g., I-cell disease/pseudo-Hurler), mucopolysaccharidoses, Sandhoff/Tysachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG1 The disease or condition is the result of and/or is associated with a disease or condition selected from the group consisting of: congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophysin-related DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases (e.g., Alzheimer's disease), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, some polyglutamine neurological disorders (e.g., Huntington's), spinal cord aneurysm type I, spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian and myotonic dystrophy, and spongiform encephalopathies (e.g., hereditary Creutzfeldt-Jakob disease) (due to prion protein processing defects), Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren's disease.

Infectious Diseases The present disclosure contemplates, among other things, the treatment of a subject having an infectious disease. The present disclosure contemplates, among other things, the treatment of a subject having a disease associated with an infection. In some embodiments, the infectious disease is a viral infection or a bacterial infection. In some embodiments, the infectious disease is a viral infection. In some embodiments, the infectious disease is a bacterial infection.

In some embodiments, the viral infection is an infection with a virus selected from the group consisting of coronavirus, influenza virus, human rhinovirus, human parainfluenza virus, human metapneumovirus, and hantavirus. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is selected from the group consisting of SARS-CoV, SARS-CoV-2, and MERS-CoV.

The present disclosure contemplates, inter alia, the treatment of subjects having a disease associated with a coronavirus. In some embodiments, the disease associated with a coronavirus is selected from the group consisting of coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). In some embodiments, the disease associated with a coronavirus is selected from the group consisting of COVID-19. In some embodiments, the coronavirus is selected from the group consisting of SARS-CoV-1, SARS-CoV-2, and 2012-nCoV. In some embodiments, the coronavirus is SARS-CoV-2.

In some embodiments, the bacterial infection is an infection with a bacterium selected from the group consisting of Streptococcus pneumoniae, Chlamydia pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Haemophilus influenzae. In some embodiments, the Staphylococcus aureus is methicillin-resistant Staphylococcus aureus.

In order to provide a more complete understanding of the invention described herein, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed in any way as limiting the scope thereof.

Materials and Methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or suitable process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise indicated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T. W. Greene and P. G. M. Wuts, *Protecting Groups in Organic Synthesis*, Second Edition, Wiley, New York, 1991, and references cited therein.

The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include (but are not limited to) trituration, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details regarding the preparation of representative oxysterols listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation/purification of enantiomers/diastereomers provided herein include, but are not limited to, ChiralPak® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

It will be understood that ^{the 1} H-NMR reported herein (e.g., for the region between δ (ppm) of about 0.5 and about 4 ppm) is an exemplary interpretation of the NMR spectrum of the compound (e.g., exemplary peak integrations).

LC-ELSD/MS: (Mobile phase: 1.5ML/4L TFA in water (solvent A) and 0.75ML/4L TFA in acetonitrile (solvent B), elution gradient 30%-90% (solvent B) over 0.9 minutes, held at 90% for 0.6 minutes at a flow rate of 1.2ml/min; Column: Xtimate C18 2.1*30mm, 3um; Wavelength: UV 220nm; Column temperature: 50°C; MS ionization: ESI; Detector: PDA & ELSD.

Abbreviations:
PE: petroleum ether, EtOAc: ethyl acetate, THF: tetrahydrofuran, PCC: pyridinium chlorochromate, TLC: thin layer chromatography, PCC: pyridinium chlorochromate, t-BuOK: potassium tert-butoxide, 9-BBN: 9-borabicyclo[3.3.1]nonane, Pd(t-Bu ₃ P) ₂ : bis(tri-tert-butylphosphine)palladium(0), AcCl: acetyl chloride, i-PrMgCl: isopropylmagnesium chloride; TBSCl: tert-butyl(chloro)dimethylsilane, (i-PrO) ₄ Ti: titanium tetraisopropoxide, BHT: 2,6-di-t-butyl-4-methylphenoxide, Me: methyl, i-Pr: isopropyl, t-Bu: tertiary butyl, Ph: phenyl, Et: ethyl, Bz: benzoyl, BzCl: benzoyl chloride, CsF: cesium fluoride, DCC: dicyclohexylcarbodiimide, DCM: dichloromethane, DMAP: 4-dimethylaminopyridine, DMP: Dess-Martin periodinane, EtMgBr: ethyl magnesium bromide, EtOAc: ethyl acetate, TEA: triethylamine, AlaOH: alanine, Boc: t-butoxycarbonyl. Py: pyridine, TBAF: tetra-n-butylammonium fluoride, THF: tetrahydrofuran, TBS: t-butyldimethylsilyl, TMS: trimethylsilyl, TMSCF ₃ : (trifluoromethyl)trimethylsilane, Ts: p-toluenesulfonyl, Bu: butyl, Ti(OiPr) ₄ : tetraisopropoxytitanium, LAH: lithium aluminum hydride, LDA: lithium diisopropylamide, LiOH. H ₂ O: lithium hydroxide hydrate, MAD: methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide), MeCN: acetonitrile, NBS: N-bromosuccinimide, Na ₂ SO ₄ : sodium sulfate, Na ₂ S ₂ O ₃ : sodium thiosulfate, MeCN: acetonitrile, MeOH: methanol, Boc: t-butoxycarbonyl, MTBE: methyl tertiary butyl ether, K-Selectride: potassium tri(s-butyl)borohydride, 9-BBN dimer: 9-borabicyclo(3.3.1)nonane (dimer), DIPEA: diisopropylethylamine, DMF: dimethylformamide, FA: formic acid, SM: starting material.

Examples 1 and 2: Synthesis of 1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aS,8R,10aS,10bR,12aS)-8-hydroxy-12a-methyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile and 1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aS,8R,10aS,10bR,12aS)-8-hydroxy-12a-methyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile
Synthesis of 1.2 To a solution of (5α)-estrane-3,17-dione, 1.1 (20 g, 72.8 mmol) in THF (200 mL) was added n-PrMgCl (109 mL, 218 mmol, 2 M in THF) dropwise at −60° C. After stirring at −60° C. for 2 h, the reaction mixture was poured into saturated aqueous NH ₄ Cl solution (400 mL) at 0° C. and extracted with EtOAc (2×200 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated, and purified by silica gel column (PE/EtOAc=0-20%) to give 1.2 (18.4 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.43 (dd, J = 8.8, 19.3 Hz, 1H), 2.16-2.00 (m, 1H), 1.97-1.85 (m, 2H), 1.83-1.72 (m, 3H), 1.68-1.43 (m, 5H), 1.40-0.89 (m, 17H), 0.87 (s, 3H), 0.79-0.61 (m, 2H).

Synthesis of 1.3 To a solution of diisopropylamine (19.4 mL, 0.718 g/mL, 139 mmol) in THF (64 mL) was added n-butyl-lithium (55.6 mL, 2.5 M in hexanes, 139 mmol) at −78° C. After stirring for 10 min at −78° C., the LDA solution was added to a solution of 1.2 (11.7 g, 36.7 mmol) and ethyl diazoacetate (20.8 g, 183 mmol) in THF (400 mL) at −78° C. After stirring for 2 h at −78° C., the reaction was quenched with acetic acid (10.9 g, 183 mmol) in THF (50 mL), stirred at 15° C. for 16 h, poured into water (1000 mL), and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (1500 mL), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give 1.3 (20 g) as an oil which was used as is.

Synthesis of 1.4 To a solution of 1.3 (20 g) and DME (200 mL) was added _Rh2 (OAc) ₄ (204 mg, 0.462 mmol) in one portion at 15° C. After stirring at 15° C. for 2 h, the reaction mixture was concentrated to give 1.4 (20 g) as an oil, which was used as is.

Synthesis of 1.5 To a solution of 1.4 (20 g) in MeOH (200 mL) was added KOH (27.7 g, 494 mmol) at 15° C. After heating at 70° C. for 1 h, the reaction mixture was poured into H ₂ O (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with HCl (1 M, 100 mL), saturated NaHCO ₃ (100 mL), brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash®-combi (0-15% EtOAc in PE) to give 1.5 (4.0 g) as a solid. ^1H NMR (400 MHz, _CDCl3 ) _δH 2.62 (dt, J=6.8, 14.1 Hz, 1H), 2.19 (br d, J=10.3 Hz, 1H), 2.05 (dt, J=2.6, 6.6 Hz, 1H), 1.93-1.57 (m, 8H), 1.54-1.12 (m, 12H), 1.12-1.05 (m, 4H), 1.05-0.84 (m, 7H), 0.65 (br dd, J=2.8, 10.8 Hz, 2H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₂ H ₃₅ O[M−H ₂ O+H] ⁺ 315.2 found 315.2.

Synthesis of 1.6: To a suspension of _Ph3PEtBr (10.6 g, 28.8 mmol) in anhydrous THF (50 mL) was added t-BuOK (4.84 g, 43.2 mmol) under _N2 at 15 °C. After stirring at 45 °C for 30 min, a solution of 1.5 (4.8 g, 14.4 mmol) in anhydrous THF (50 mL) was added dropwise. After stirring at 45 °C for 16 h, the reaction mixture was cooled, poured into ice-water (100 mL), stirred for 10 min, and extracted with EtOAc (2 × 100 mL). The combined organic phase was washed with saturated brine (2 × 200 mL), filtered, and concentrated. The residue was purified by flash column (0-10% EtOAc in PE) to give 1.6 (1.8 g, 36.2%) as a solid and recovered starting material 1.5 (1.2 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 5.15 (br t, J = 6.5 Hz, 1H), 2.50 (br d, J = 13.8 Hz, 1H), 2.25-2.06 (m, 1H), 2.02-1.59 (m, 9H), 1.41-1.02 (m, 14H), 0.95-0.61 (m, 4H).

Synthesis of 1.7 To a solution of 1.6 (1.8 g, 5.22 mmol) in THF (50 mL) was added 9-BBN dimer (3.80 g, 15.6 mmol) at 15° C. After stirring at 50° C. for 16 h, the reaction mixture was cooled and diluted sequentially with EtOH (6.05 mL, 104 mmol, 0.789 g/mL), dropwise NaOH (20.8 mL, 5 M, 104 mmol), and dropwise H ₂ O ₂ (11.7 g, 104 mmol, 30% in water) at 0° C. to maintain the internal temperature below 30° C. After stirring at 50° C. for 1 h, the reaction mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ (130 mL). After stirring at 0° _C for an additional 1 h, the reaction was checked by potassium iodide-starch test paper to ensure excess _H2O2 was destroyed. The aqueous phase was extracted with DCM (3 x 50 mL). The combined organic phases were washed with saturated _Na2S2O3 (2 x 100 mL), _brine (2 x 100 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure to give 1.7 (800 mg) _as a solid.

Synthesis of 1.8 To a solution of 1.7 (800 mg, 2.20 mmol) in DCM (30 mL) was added DMP (1.86 g, 4.40 mmol) at 25° C. After stirring at 25° C. for 1 h, the mixture was diluted with _NaHCO (50 mL ₎ and Na _{S O} (50 mL, saturated) and extracted with DCM ( ₂ ×50 mL). The combined organic phase was washed with NaHCO (100 mL), _{Na S O} (100 mL, saturated), and brine (100 mL), dried _{over anhydrous Na} SO , filtered, concentrated, dried over _Na SO , filtered, and concentrated. The residue was purified by flash column (0-15% EtOAc in PE) to give 1.8 (740 mg) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.32 (dd, J = 3.3, 12.5 Hz, 1H), 2.18-2.13 (m, 4H), 1.92-1.66 (m, 9H), 1.46-1.20 (m, 12H), 1.11-0.67 (m, 14H).

Synthesis of 1.8a and 1.8b To a solution of 1.8 (5.8 g, 16.0 mmol) in MeOH (100 mL) was added MeONa (12.9 g, 240 mmol) at 0° C. After stirring at 70° C. for 16 h, the reaction mixture was added to saturated NH ₄ Cl (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue (200 mg) was purified by column (0-3% acetone in DCM) to give both 1.8a (69.3 mg, 34.8%) and 1.8b (16.0 mg, 8.04%) as solids.
1.8a: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.30 (dd, J=3.3, 12.8 Hz, 1H), 2.14 (s, 3H), 1.86-1.59 (m, 8H), 1.51-1.21 (m, 9H), 1.15-0.89 (m, 14H), 0.87-0.50 (m, 5H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₄ H ₃₉ O[MH ₂ O+H] ⁺ 343.3 found 343.3.
1.8b: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.47 (d, J = 5.9 Hz, 1H), 2.12 (s, 3H), 1.74 (br d, J = 12.5 Hz, 7H), 1.51-1.19 (m, 12H), 1.16-0.74 (m, 16H), 0.68-0.51 (m, 1H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₄ H ₃₉ O[MH ₂ O+H] ⁺ 343.3 found 343.3.

Synthesis of 1.9. To a suspension of _MePh3PBr (4.31 g, 12.2 mmol) in anhydrous THF (20 mL) was added t-BuOK (1.36 g, 12.2 mmol) under _N2 at 15 °C. After stirring at 40 °C for 30 min, a solution of 1.8a (2.2 g, 6.10 mmol) in anhydrous THF (20 mL) was added dropwise. After stirring at 40 °C for 16 h, the mixture was cooled, poured into ice-water (150 mL), stirred for 10 min, and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with saturated brine (2 × 100 mL), filtered, and concentrated. The residue was purified by flash column (0-10% EtOAc in PE) to give 1.9 (1.9 g, 87.1%) as a solid. ¹ H NMR (400 MHz, CDCl3) δH 4.80 (s, 1H), 4.61 (d, J = 2.0 Hz, 1H), 1.76 (br s, 4H), 1.73-1.47 (m, 11H), 1.37-1.18 (m, 7H), 1.13-0.84 (m, 12H), 0.83 (s, 3H), 0.81-0.53 (m, 3H).

Synthesis of 1.10 To a solution of 1.9 (700 mg, 1.95 mmol) in DCM (10 mL) was added m-CPBA (790 Mg, 85%, 3.90 mmol) at 0° C. After stirring at 25° C. for 1 h, the mixture was quenched with _NaHCO (50 mL, saturated aqueous solution) and Na _{S O} (20 _mL , saturated aqueous solution). The organic layer was separated, dried _{over Na} SO , filtered, and concentrated. The residue was purified by flash column (0-10% EtOAc in PE) to give 1.10 (340 mg, 46.5%) as a solid. ¹ H NMR (400 MHz, CDCl3) δH 2.77-2.55 (m, 2H), 1.82-1.65 (m, 8H), 1.54-1.47 (m, 2H), 1.47-1.25 (m, 8H), 1.06-0.88 (m, 16H), 0.84-0.56 (m, 5H), 0.55-0.54 (m, 1H).

Synthesis of 1 and 2 To a solution of 1.10 (340 mg, 0.908 mmol) in DMF (10 mL) was added 1H-pyrazole-4-carbonitrile (168 mg, 1.81 mmol) and Cs ₂ CO ₃ (593 mg, 1.81 mmol) at 20° C. After stirring at 120° C. for 2 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were concentrated and purified by flash column (30-50% EtOAc in PE) to give a diastereomeric mixture of 1 and 2 (350 mg) as a solid. The diastereomers were separated by SFC (column DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 μm) conditions: 0.1% NH ₃ H ₂ O EtOH Start B 30% End B 30% Gradient time (min) 100% B Retention time (min) Flow rate (ml/min) 50) to give both 2 (208.9 mg) and 1 (50.2 mg) as solids.

1: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.88 (s, 1H), 7.83 (s, 1H), 4.27 (d, J = 14.0 Hz, 1H), 4.00 (d, J = 13.9 Hz, 1H), 3.00 (s, 1H), 2.36 (br d, J=12.8 Hz, 1H), 1.95-1.56 (m, 5H), 1.42-1.35 (m, 6H), 1.28-1.22 (m, 3H), 1.18 (s, 3H), 1.15-1.05 (m, 5H), 1.01 (s, 3H), 0.95-0.88 (m, 8H), 0.88-0.56 (m, 6H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₉ H ₄₂ N ₃ [M-2H ₂ O+H] ⁺ 432.4 found 432.4.

2: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.92 (s, 1H), 7.79 (s, 1H), 4.52-4.13 (m, 2H), 2.47 (br s, 1H), 2.30 (br d, J = 13.0 Hz, 1H), 1.91-1.68 (m, 7H), 1.45-1.20 (m, 12H), 1.15-1.03 (m, 2H), 1.00-0.70 (m, 17H), 0.66-0.53 (m, 1H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₉ H ₄₂ N ₃ [M-2H ₂ O+H] ⁺ 432.3 found 432.3.

Examples 6 and 7: Synthesis of 1-((R)-2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-ethyl-8-hydroxy-12a-methyloctadecahydrochrysen-1-yl)-2-hydroxypropyl-1H-pyrazole-4-carbonitrile and 1-((S)-2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-ethyl-8-hydroxy-12a-methyloctadecahydrochrysen-1-yl)-2-hydroxypropyl-1H-pyrazole-4-carbonitrile
Synthesis of 6.2 To a solution of BHT (144 g, 654 mmol) in toluene (165 mL) was added AlMe ( ₂ M in toluene, 163 mL, 327 mmol) dropwise at 0°C under nitrogen. After stirring at 25°C for 1 h, the MAD solution was used without further purification. To a solution of MAD (327 mmol) was added dropwise a solution of (5β)-estrane-3.17-dione, 6.1 (30 g, 109 mmol) in DCM (100 mL) at −70°C. After stirring at −70°C for 1 h under _N , EtMgBr (130 mL, 327 mmol, 2.5 M in ethyl ether) was added dropwise at −70°C. After stirring at −70°C for an additional 2 h, the reaction mixture was poured into saturated aqueous citric acid (100 mL) at 10°C and extracted with DCM (2 × 40 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc = 0-20%) to give 6.2 (25 g, 76%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.50-2.36 (m, 1H), 2.14-2.01 (m, 1H), 1.97-1.88 (m, 1H), 1.84-1.74 (m, 4H), 1.68-1.45 (m, 7H), 1.43-0.97 (m, 12H), 0.92-0.82 (m, 6H).

Synthesis of 6.3 To a solution of DIPA (34.7 g, 343 mmol) in THF (190 mL) was added BuLi (124 mL, 2.5 M in hexanes, 312 mmol) at −70° C. After warming to 0° C. and stirring for 1 h, cold (−70° C.) LDA solution (312 mL, 1.0 M, 312 mmol) was added to a stirred solution of 6.2 (19 g, 62.4 mmol) and ethyl diazoacetate (35.5 g, 312 mmol) in THF (100 mL) at −78° C. After stirring for 1 h at −70° C., the reaction mixture was quenched with acetic acid (18.7 g, 312 mmol) in THF (50 mL), warmed to 20° C., diluted with water (300 mL), and extracted with EtOAc (3×400 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by flash column (0-5% EtOAc in PE) to give 6.3 (6 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 4.80 (m, 1H), 4.33-4.19 (m, 2H), 2.20-2.08 (m, 1H), 1.93-1.54 (m, 9H), 1.50-1.28 (m, 12H), 1.19-0.98 (m, 5H), 0.95-0.81 (m, 6H).

Synthesis of 6.4 To a solution of 6.3 (6.0 g, 14.3 mmol) in DME (30 mL) was added _Rh2 (OAc) ₄ (94.7 mg, 0.2 mmol) at 25° C. After stirring at 25° C. for 12 h, the reaction mixture was concentrated to give 6.4 (6 g) as a solid, which was used as is.

Synthesis of 6.5 To a mixture of 6.4 (6.00 g, 15.3 mmol) in MeOH/THF (30 mL/30 mL) was added KOH (8.58 g, 153 mmol). After stirring at 70° C. for 12 h, the reaction mixture was extracted with ethyl acetate (4×80 mL). The combined organic phases were washed with water (80 mL), brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column (15-30% EtOAc in PE) to give 6.5 (3.9 g, 80%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.69-2.53 (m, 1H), 2.23-2.14 (m, 1H), 2.08-1.99 (m, 1H), 1.87-1.58 (m, 10H), 1.54-1.21 (m, 12H), 1.19-0.93 (s, 6H), 0.90-0.79 (m, 3H).

Synthesis of 6.6. To a suspension of _Ph3PEtBr (13.5 g, 36.5 mmol) in anhydrous THF (100 mL) was added t-BuOK (5.47 g, 48.8 mmol) under _N2 at 15 °C. After stirring at 40 °C for 30 min, a solution of 6.5 (3.9 g, 12.2 mmol) in anhydrous THF (50 mL) was added dropwise. After stirring for 16 h, the mixture was cooled, poured into ice-water (150 mL), stirred for 10 min, and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with saturated brine (2 × 200 mL), filtered, and concentrated. The residue was purified by flash column (10% to 30% ethyl ether in PE) to give 6.6 (3.1 g, 77%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 5.52-5.09 (m, 1H), 2.30-2.09 (m, 1H), 1.89-1.57 (m, 14H), 1.51-1.19 (m, 10H), 1.12-1.02 (m, 3H), 1.00-0.83 (m, 8H).

Synthesis of 6.7 To _{a solution of 6.6 (3.1 g, 9.4 mmol) in THF (10 mL) was added BH3.Me2S (} 2.81 mL, 28.1 mmol) at 0°C. After stirring at 15°C for 12 h, the reaction mixture was cooled and quenched with EtOH (5.46 mL, 93.7 mmol, 0.789 g/mL) at 0° _C and NaOH (18.7 mL, 5 M, 93.7 mmol) sequentially. _H2O2 (9.38 mL, 93.7 mmol, 1.13 g/mL, 30% in water) was then added slowly until the internal temperature no longer rose, maintaining the internal temperature below 30°C. After stirring at 50° C. for an additional 1 h, the reaction mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ (50 mL), stirred at 0° C. for 1 h, and extracted with DCM (3×50 mL). The combined organic phases were washed with saturated Na ₂ S ₂ O ₃ (2×50 mL), brine (2×50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 6.7 (3.26 g) as a solid, which was used as is.

Synthesis of 6.8: To a mixture of 6.7 (3.26 g, 9.35 mmol) and silica gel (5 g) in DCM (15 mL) was added PCC (3.01 g, 14.0 mmol) in portions. After stirring at 15° C. for 1 h, the reaction mixture was filtered, and the filtrate was concentrated to give 6.8 (3.24 g) as an oil.

Synthesis of 6.8a To a solution of 6.8 (2 g, 5.8 mmol) in MeOH (20 mL) was added MeONa (4.67 g, 86.5 mmol) at 0° C. After stirring at 70° C. for 16 h, the reaction mixture was added to saturated NH ₄ Cl (20 mL) and extracted with EtOAc (2×20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give 6.8a (1.5 g) as a solid.

Synthesis of 6.9 To a mixture of MePPh ₃ Br (3.07 g, 8.63 mmol) in THF (12 mL) was added t-BuOK (966 mg, 8.63 mmol) under N ₂ at 15°C. After stirring at 50°C for 30 min, 6.8a (1 g, 2.88 mmol) in THF (8 mL) was added portionwise below 50°C. After stirring at 50°C for 1 h, the reaction mixture was quenched with 10% aqueous NH ₄ Cl (30 mL) at 15°C and extracted with EtOAc (2 × 30 mL). The combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/PE = 0-15%) to give 6.9 (720 mg, 72.5%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 4.80 (s, 1H), 4.62-4.58 (m, 1H), 1.86-1.58 (m, 5H), 1.57-1.50 (m, 6H), 1.49-1.39 (m, 3H), 1.38-1.23 (m, 6H), 1.22-1.15 (m, 2H), 1.14-0.85 (m, 10H), 0.84-0.83 (m, 3H), 0.82 (s, 3H).

Synthesis of 6.10 To a solution of 6.9 (720 mg, 2.08 mmol) in DCM (5 mL) was added m-CPBA (893 mg, 4.16 mmol, 80%) at 15° C. After stirring at 15° C. for 1 h, the mixture was quenched with saturated NaHCO ₃ and Na ₂ S ₂ O ₃ (10 mL, v:v=1:1) and extracted with DCM (2×10 mL). The combined organic phase was washed with saturated NaHCO ₃ and Na ₂ S ₂ O ₃ (10 mL, v:v=1:1), dried over Na ₂ SO ₄ , filtered, and concentrated to give 6.10 (900 mg) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 8.07-8.04 (m, 1H), 8.03-7.95 (m, 1H), 7.66-7.52 (m, 1H), 7.50-7.35 (m, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 2.70-2.60 (m, 2H), 1.85-1.65 (m, 6H), 1.64-1.50 (m, 6H), 1.49-1.26 (m, 4H), 1.25-2.60 (m, 5H), 1.20-0.85 (m, 10H).

Synthesis of 6 and 7. To a solution of 6.10 (900 mg, 2.49 mmol) in DMF (5 mL) was added Cs ₂ CO ₃ (2.43 g, 7.47 mmol) and 1H-pyrazole-4-carbonitrile (579 mg, 6.22 mmol). After stirring at 130° C. for 12 h, the mixture was added to saturated NH ₄ Cl (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with LiCl (10 mL, 5% in water), saturated brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give a mixture of diastereomers 6 and 7 (670 mg) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.98 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 4.25-4.211 (m, 2H), 2.50 (m, 2H), 2.38-2.30 (m, 1H), 2.05 (s, 3H), 1.73-1.60 (m, 6H), 1.59-1.52 (m, 5H), 1.51-1.47 (m, 5H), 1.46-1.24 (m, 3H), 1.23 (s, 1H), 1.00-0.88 (m, 6H), 0.87-0.85 (m, 6H).

The diastereomers (670 mg) were separated by SFC (DAICEL CHIRALCEL OJ-H (250 mm * 30 mm, 5 um), conditions: 0.1% NH ₃ H ₂ O EtOH, start B: 25%, end B: 25%, flow rate (ml/min): 60) to give 6 (212.6 mg, 31.8%) and 7 (55 mg) as solids. 7 was further purified by SFC (Column: DAICEL CHIRALCEL OJ-H (250 mm * 30 mm, 5 um), conditions: 0.1% NH ₃ H ₂ O EtOH, start B: 25%, end B: 25%, flow rate (ml/min): 60) to give 7 (33.5 mg) as a solid.

6: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.92 (s, 1H), 7.80 (s, 1H), 4.39-4.20 (m, 2H), 2.45-2.25 (m, 2H), 1.74-1.62 (m, 7H), 1.61-1.55 (m, 6 H), 1.54-1.48 (m, 7H), 1.47-1.35 (m, 6H), 1.35-1.25 (m, 4H), 1.05-0.95 (m, 4H), 0.90-0.85 (m, 3H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₈ H ₄₀ N ₃ [M-2H ₂ O+H] ⁺ 418 found 418. SFC 99% de.

7: ^1H NMR (400 MHz, _CDCl3 ) _δH 7.88 (s, 1H), 7.86 (s, 1H), 4.30-4.24 (m, 1H), 4.01-3.95 (m, 1H), 3.05 (s, 1H), 2.42-2.38 (m, 1H), 1.84-1.74 (m, 2H), 1.73-1.45 (m, 9H), 1.44-1.19 (m, 11H), 1.18-1.00 (m, 6H), 0.99-0.86 (m, 9H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₈ H ₄₀ N ₃ [M-2H ₂ O+H] ⁺ 418 found 418. SFC 100% de.

Examples 8 and 9: Synthesis of 1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-12a-methyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile and 1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-12a-methyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile
Synthesis of 8.2 To a solution of BHT (96 g, 436 mmol) in toluene (300 mL) was added AlMe ( ₂ M in toluene, 109 mL, 218 mmol) dropwise at 0°C under nitrogen. After stirring at 25°C for ₁ h, the MAD solution was used directly without further purification. To a freshly prepared solution of MAD (218 mmol) was added dropwise a solution of 6.1 (20 g, 72.8 mmol) in DCM (80 mL) at −70°C. After stirring at −70°C for 1 h under N, n-PrMgCl (72.5 mL, 145 mmol, 2 M in ethyl ether) was added dropwise at −70°C. After stirring at −70°C for 2 h, the reaction mixture was poured into saturated aqueous citric acid (100 mL) at 10°C and extracted with EtOAc (2 × 400 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give 8.2 (12 g, 52%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.44 (dd, J = 8.5, 19.3 Hz, 1H), 2.15-2.07 (m, 1H), 2.13-2.00 (m, 1H), 1.98-1.88 (m, 1H), 1.86-1.59 (m, 6H), 1.54-1.00 (m, 18H), 0.93 (t, J = 7.2 Hz, 3H), 0.87 (s, 3H).

Synthesis of 8.3: To a solution of 8.2 (12.0 g, 37.6 mmol) and ethyl diazoacetate (19.7 mL, 188 mmol, 1.085 g/mL) in THF (800 mL) was added freshly prepared LDA (180 mL, 1.0 M, 180 mmol) at −78° C. After stirring at −78° C. for 2 h, the reaction mixture was quenched with acetic acid (10.6 mL, 188 mmol) in THF (50 mL), stirred at 15° C. for 16 h, poured into water (1000 mL), and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (1500 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated under reduced pressure. The residue was purified by flash column (0-10% EtOAc in PE) to give 8.3 (13 g, 80%) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 4.29-4.19 (m, 2H), 2.23-2.08 (m, 1H), 1.96-1.59 (m, 8H), 1.53-1.28 (m, 17H), 1.17-1.02 (m, 5H), 0.96-0.90 (m, 5H), 0.86 (br d, J = 6.8 Hz, 2H).

Synthesis of 8.4 To a solution of 8.3 (13 g, 30.0 mmol) and DME (150 mL) was added _Rh2 (OAc) ₄ (132 mg, 0.3 mmol) in one portion at 15° C. After stirring at 15° C. for 2 h, the reaction mixture was concentrated to give 8.4 (13 g) as an oil, which was used as is.

Synthesis of 8.5 To a solution of 8.4 (13 g, 32.1) in MeOH (200 mL) was added KOH (18.0 g, 321 mmol) at 15° C. After stirring at 70° C. for 1 h, the reaction mixture was poured into H ₂ O (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with HCl (1 M, 100 mL), saturated NaHCO ₃ (100 mL), brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-15% EtOAc in PE) to give 8.5 (8.3 g, 78.3%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.61 (dt, J = 6.8, 13.9 Hz, 1H), 2.27-2.15 (m, 1H), 2.08-2.02 (m, 1H), 1.87-1.49 (m, 13H), 1.48-1.20 (m, 12H), 1.18-1.10 (m, 1H), 1.08 (s, 3H), 1.03-0.96 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H).

Synthesis of 8.6 To a suspension of _Ph3PEtBr (27.6 g, 74.6 mmol) in anhydrous THF (100 mL) was added t-BuOK (11.1 g, 99.6 mmol) under _N2 at 15 °C. After stirring at 40 °C for 30 min, a solution of 8.5 (8.3 g, 24.9 mmol) in anhydrous THF (50 mL) was added dropwise. After stirring at 40 °C for 16 h, the mixture was cooled, poured into ice-water (150 mL), stirred for 10 min, and extracted with EtOAc (2 × 100 mL). The combined organic phase was washed with brine (2 × 200 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated. The residue was purified by trituration with MeOH/H ₂ O (1:1, 320 mL) under reflux to give 8.6 (5.3 g, 62%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 5.24-5.00 (m, 1H), 2.50 (br d, J = 13.8 Hz, 1H), 2.25-2.10 (m, 1H), 2.01-1.56 (m, 10H), 1.48-1.16 (m, 14H), 1.05 (s, 3H), 0.92-0.80 (m, 10H).

Synthesis of 8.7 To _a solution of 8.6 (5.3 g, 15.3 mmol) in THF (100 mL) was added _BH3.Me2S (4.58 mL, 45.9 mmol) at 0°C. After stirring at 15°C for 16 h, the reaction mixture was cooled (0°C) and treated with EtOH (8.91 mL, 203 mmol, 0.789 g/mL), _NaOH (30.5 mL, 5 M, 153 mmol), and _H2O2 (15.3 mL, 153 mmol, 1.13 g/mL, ₃₀ % in water ₎ successively and slowly, dropwise, until the internal temperature no longer rose, maintaining the internal temperature below 30°C. After stirring at 50°C for 1 h, the reaction was quenched with saturated aqueous _Na2S2O3 (130 mL) and stirred at 0°C for an additional 1 h. The reaction was checked by potassium iodide-starch test paper to ensure excess H ₂ O ₂ was destroyed (no blue color change). The aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phases were washed with saturated Na ₂ S ₂ O ₃ (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 8.7 (4.3 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H = 2.47 (br d, J = 5.2 Hz, 0.4 H), 2.29 (dd, J = 3.2, 12.8 Hz, 0.6 H), 2.13 (d, J = 3.2 Hz, 3H), 1.88-1.66 (m, 3H), 1.54-1.44 (m, 6H), 1.41-1.14 (m, 13H), 1.11-0.80 (m, 13H).

Synthesis of 8.8 To a mixture of PCC (3.70 g, 17.2 mmol) and silica gel (4 g) in DCM (20 mL) was added 8.7 (2.5 g, 6.89 mmol) in DCM (30 mL) at 25° C. After stirring at 25° C. for 1 h, the reaction mixture was filtered and washed with DCM (100 mL). The filtrate was collected and concentrated to give 8.8 (1.93 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H = 2.47 (br d, J = 5.2 Hz, 0.4 H), 2.29 (dd, J = 3.2, 12.8 Hz, 0.6 H), 2.13 (d, J = 3.2 Hz, 3H), 1.88-1.66 (m, 3H), 1.54-1.44 (m, 6H), 1.41-1.14 (m, 13H), 1.11-0.80 (m, 13H).

Synthesis of 8.9 To a solution of 8.8 (1.93 g, 5.35 mmol) in MeOH (20 mL) at 0° C. was added MeONa (4.33 g, 80.2 mmol). After stirring at 70° C. for 16 h, the reaction mixture was added to saturated NH ₄ Cl (10 mL) and extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 8.9 (1.2 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H = 2.30 (dd, J = 3.2, 12.7 Hz, 1H), 2.14 (s, 3H), 1.82 (br d, J = 12.4 Hz, 2H), 1.76-1.63 (m, 5H), 1.57-1.43 (m, 7H), 1.40-1.23 (m, 10H), 1.07-0.84 (m, 12H).

Synthesis of 8.10 To a mixture of MePPh _Br (9.46 g, 26.5 mmol) in THF (20 mL) was added t-BuOK (2.96 g, 26.5 mmol) under _N at 25°C. After stirring at 50°C for 30 min, 8.9 (1.2 g, 3.32 mmol) in THF (10 mL) was added at 25°C. After stirring at 60°C for 3 h, the reaction mixture was cooled, poured into ice-water (50 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column (0-30% EtOAc in PE) to give 8.10 (1.1 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H = 4.80 (s, 1H), 4.61 (s, 1H), 1.83 (br d, J = 14.4 Hz, 2H), 1.70-1.57 (m, 6H), 1.53-1.43 (m, 4H), 1.40-1.22 (m, 12H), 1.19-1.04 (m, 2H), 0.99-0.87 (m, 9H), 0.82 (s, 3H).

Synthesis of 8.11 To a solution of 8.10 (500 mg, 1.39 mmol) in DCM (10 mL) was added m-CPBA (446 mg, 2.08 mmol, 80%) at 25° C. After stirring at 25° C. for 2 h, the mixture was quenched with saturated NaHCO ₃ and Na ₂ S ₂ O ₃ (40 mL, v:v=1:1) and extracted with DCM (2×20 mL). The combined organic phase was washed with saturated NaHCO ₃ and Na ₂ S ₂ O ₃ (50 mL, v:v=1:1), dried over Na ₂ SO ₄ , filtered, and concentrated to give 8.11 (520 mg) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.70 (br d, J = 5.2 Hz, 1H), 2.65-2.49 (m, 1H), 1.91-1.78 (m, 7H), 1.70-1.61 (m, 10H), 1.31 (br d, J = 7.6 Hz, 10H), 0.96-0.88 (m, 14H).

Synthesis of 8 and 9. To a solution of 8.11 (300 mg, 0.8008 mmol) in DMF (5 mL) was added Cs ₂ CO ₃ (782 mg, 2.40 mmol) and 1H-pyrazole-4-carbonitrile (186 mg, 2.00 mmol). After stirring at 130° C. for 12 h, the mixture was added to saturated NH ₄ Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with LiCl (100 mL, 5% in water), brine (2×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-50% EtOAc in PE) to give a mixture of diastereomers 8 and 9 (165 mg) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H = 7.92 (s, 1H), 7.79 (s, 1H), 4.38-4.33 (m, 1H), 4.26-4.18 (m, 1H), 2.32 (br d, J = 13.2 Hz, 5H), 1.77-1.61 (m, 11H), 1.37-1.28 (m, 10H), 1.00-0.91 (m, 15H).

The C20 diastereomers were separated by SFC (column DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 μm); condition 0.1% NH ₃ H ₂ O EtOH; flow rate (ml/min) 70) to give 8 (67.3 mg, 32.2%) and 9 (11 mg) as solids. 9 (11 mg) was further purified by SFC (column DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 μm); condition 0.1% NH ₃ H ₂ O EtOH; flow rate (ml/min) 70) to give 9 (6.5 mg) as a solid.

8: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H =7.92 (s, 1H), 7.79 (s, 1H), 4.39-4.32 (m, 1H), 4.26-4.20 (m, 1H), 2.43 (s, 1H), 2.32 (br d, J = 12.8 Hz, 1H), 1.91-1.64 (m, 6H), 1.55-1.18 (m, 18H), 1.03-0.82 (m, 15H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₉ H ₄₂ N ₃ [M-2H ₂ O+H] ⁺ 432.3, found 432.3. SFC 98.54% de.

9: ^1H NMR (400 MHz, _CDCl3 ) _δH =7.88 (s, 1H), 7.85 (s, 1H), 4.31-4.24 (m, 1H), 4.02-3.96 (m, 1H), 3.0 6 (s, 1H), 2.43-2.34 (m, 1H), 1.85-1.73 (m, 2H), 1.70-1.59 (m, 4H), 1. 54-1.42 (m, 12H), 1.36-1.30 (m, 3H), 1.30-1.23 (m, 5H), 1.18 (s, 1H), 1.16-1.04 (m, 2H), 1.00 (s, 1H), 0.95-0.87 (m, 6H), 0.86-0.71 (m, 3H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₉ H ₄₂ N ₃ [M-2H ₂ O+H] ⁺ 432.3, found 432.3. SFC 99.02% de.

Examples 10 and 11: Synthesis of 1-((S)-2-((1S,4aS,4bR,6aS,8R,10aS,10bR,12aS)-8-ethyl-8-hydroxy-12a-methyloctadecahydrochrysen-1-yl)-2-hydroxypropyl-1H-pyrazole-4-carbonitrile and 1-((R)-2-((1S,4aS,4bR,6aS,8R,10aS,10bR,12aS)-8-ethyl-8-hydroxy-12a-methyloctadecahydrochrysen-1-yl)-2-hydroxypropyl-1H-pyrazole-4-carbonitrile
Synthesis of 10.2 To a solution of 1.1 (50 g, 182 mmol) in MeOH (600 mL) was added 4-methylbenzenesulfonic acid (6.26 g, 36.4 mmol) at 25° C. After stirring at 55° C. for 16 h, the mixture was diluted with Et ₃ N (20 mL). The solid was filtered and the filtrate was concentrated to give 10.2 (52 g, 89.1%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 0.73-0.83 (m, 1 H), 0.91 (s, 3 H), 0.98-1.13 (m, 2 H), 1.20-1.56 (m, 16 H), 1.72-1.78 (m, 1 H), 1.80-1.86 (m, 2 H), 1.88-1.99 (m, 2 H), 2.05-2.16 (m, 2 H), 2.25-2.35 (m, 3 H), 2.38-2.51 (m, 2 H), 3.15 (s, 1 H), 3.21 (s, 1 H), 3.50 (s, 6 H).

Synthesis of 10.3: To a solution of 10.2 (4.5 g, 14.0 mmol) and ethyl diazoacetate (7.35 g, 1.085 g/mL, 70.0 mmol) in THF (300 mL) was added freshly prepared LDA (67.1 mL, 1.0 M, 67.1 mmol) at −78° C. After stirring for 2 h at −78° C., the reaction was quenched with acetic acid (4.00 mL, 1.0492 g/mL, 70.0 mmol) in THF (100 mL). After stirring for 16 h at 15° C., the mixture was added to NH ₄ Cl (200 mL) and extracted with EtOAc (2×125 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-10% EtOAc in PE) to give 10.3 (3.7 g, 60.8%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 4.77-4.64 (m, 1H), 4.25 (dq, J = 1.6, 7.2 Hz, 2H), 3.20 (s, 3H), 3.14 (s, 3H), 2.22-2.01 (m, 2H), 1.96-1.76 (m, 4H), 1.69-1.61 (m, 2H), 1.55-1.42 (m, 1H), 1.41-1.27 (m, 5H), 1.27-0.96 (m, 9H), 0.93 (s, 3H), 0.91-0.83 (m, 1H), 0.80-0.62 (m, 2H).

Synthesis of 10.4 To a solution of 10.3 (57 g, 147 mmol) and DME (500 mL) was added _Rh2 (OAc) ₄ (800 mg, 1.81 mmol) in one portion at 15° C. After stirring at 15° C. for 2 h, the reaction mixture was concentrated to give 10.4 (59.7 g) as an oil, which was used as is.

Synthesis of 10.5 To a solution of 10.4 (59.7 g) in MeOH (500 mL) was added KOH (81.9 g, 1460 mmol) at 15° C. After stirring at 70° C. for 1 h, the reaction mixture was poured into H ₂ O (500 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with HCl (1 M, 100 mL), saturated NaHCO ₃ (100 mL), and brine (200 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-15% EtOAc in PE) to give 10.5 (30 g, 61.4%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 3.21 (d, J = 1.2 Hz, 3H), 3.15 (d, J = 1.6 Hz, 3H), 2.24-2.01 (m, 3H), 1.98-1.78 (m, 5H), 1.76-1.61 (m, 2H), 1.59-1.13 (m, 8H), 1.10 (d, J = 6.4 Hz, 3H), 1.08-0.82 (m, 5H), 0.78-0.62 (m, 2H).

Synthesis of 10.6 To a mixture of EtPPh _Br (99.4 g, 268 mmol) in THF (400 mL) was added t-BuOK (30.0 g, 268 mmol) under _N at 15°C. After stirring at 15°C for 30 min, 10.5 (30 g, 89.6 mmol) in THF (100 mL) was added. After stirring at 40° _C for 1 h, the mixture was poured into saturated aqueous NH _Cl (400 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous _Na SO , filtered, and concentrated to give 10.6 as a residue, which was used directly in the next step.

Synthesis of 10.7 To a solution of 10.6 (31 g, 89.4 mmol) in THF (300 mL) was added HCl (89.4 mL, 1 M, 89.4 mmol). After stirring at 15 °C for 2 h, the mixture was poured into aqueous NaHCO ₃ (200 mL) and extracted with EtOAc (2 × 150 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-3% EtOAc in PE) to give 10.7 (14 g, 52.2%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 5.25-5.07 (m, 1H), 2.45-2.36 (m, 1H), 2.35-2.12 (m, 4H), 2.07 (t, J = 13.2 Hz, 1H), 1.95-1.81 (m, 3H), 1.80-1.64 (m, 5H), 1.27-1.08 (m, 9H), 0.99-0.93 (m, 2H), 0.93-0.74 (m, 6H).

Synthesis of 10.8. A stirred solution of trimethylsulfoxonium iodide (10.2 g, 46.5 mmol) and t-BuOK (6.81 g, 55.8 mmol) in DMSO (60 mL) and THF (20 mL) was heated at 40 °C for ₁ h under N. The reaction mixture was added to 10.7 (14 g, 46.5 mmol) in DMSO (20 mL). After stirring at 40 °C for 30 min, the reaction was diluted with water (250 mL) to give a solid. The precipitate was filtered and dried under reduced pressure to give 10.8 (12.5 g, 85.6%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 5.32-5.01 (m, 1H), 2.64 (s, 2H), 2.55-2.48 (m, 1H), 2.28-2.10 (m, 1H), 2.03-1.96 (m, 1H), 1.90-1.80 (m, 3H), 1.80-1.58 (m, 7H), 1.47-1.21 (m, 4H), 1.12 (br s, 4H), 1.10-1.01 (m, 3H), 0.95 (s, 2H), 0.92-0.64 (m, 5H).

Synthesis of 10.9. To a suspension of CuCN (4.21 g, 47.4 mmol) in THF (120 mL) at −40° C. was added MeLi (59.2 mL, 94.8 mmol, 1.6 M). After stirring at −40° C. for 1 h, 10.8 (5 g, 15.8 mmol) in THF (30 mL) was added at −40° C. After stirring at 25° C. for 2 h, the reaction was slowly poured into 10% NH ₄ Cl (20 mL) and extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 10.9 (4.5 g, 86.2%) as a solid. ¹ H NMR (400 MHz, CDCl3) δ _H 5.23-5.05 (m, 1H), 2.30-2.09 (m, 1H), 2.04-1.70 (m, 7H), 1.56-1.39 (m, 4H), 1.39-1.23 (m, 4H), 1.22-0.95 (m, 10H), 0.95-0.83 (m, 8H), 0.83-0.55 (m, 3H).

Synthesis of 10.10 To _a solution of 10.9 (5.5 g, 16.6 mmol) in THF (100 mL) was added _BH3Me2S (4.97 mL, 49.8 mmol, 10 M) at 0 °C. After stirring at 20 °C for 12 h, the resulting mixture was treated with ethanol (20 mL) and aqueous NaOH (33.2 mL, 5.0 M) at 0 °C. Hydrogen peroxide (19.9 mL, 10 M) was then added dropwise at 0 °C. After stirring for ₂ h, the reaction was quenched with saturated aqueous _Na2S2O3 ( ₃₀ mL) and extracted with EtOAc (2 × 30 mL). The combined organic phase was washed with brine (2 × 20 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated to give 10.10 (5.5 g, 95.1%) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 1.95-1.73 (m, 5H), 1.72-1.55 (m, 7H), 1.54-1.39 (m, 5H), 1.21-1.04 (m, 7H), 1.04-0.96 (m, 5H), 0.94-0.84 (m, 6H), 0.83-0.55 (m, 5H).

Synthesis of 10.11 To a solution of 10.10 (5.5 g, 15.7 mmol) in DCM (100 mL) was added PCC (10.1 g, 47.0 mmol) and silica gel (12 g) at 25° C. After stirring at 25° C. for 1 h, the reaction mixture was filtered and the filter cake was washed with DCM (2×20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column (15-20% EtOAc in PE) to give 10.11 (4.4 g, 81.4%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.50-2.25 (m, 1H), 2.17-2.09 (m, 3H), 1.87-1.67 (m, 6H), 1.50-1.38 (m, 4H), 1.36-1.17 (m, 5H), 1.17-0.94 (m, 7H), 0.93-0.92 (m, 3H), 0.91-0.87 (m, 4H), 0.87-0.54 (m, 5H).

Synthesis of 10.12 To a solution of 10.11 (1.4 g, 4.03 mmol) in MeOH (50 mL) was added MeONa (3.26 g, 60.4 mmol) at 0 °C. After stirring at 70 °C for 16 h, the reaction mixture was added to saturated NH ₄ Cl (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 10.12 (1.2 g, 86.3%) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.31 (dd, J = 3.2, 12.8 Hz, 1H), 2.15 (s, 3H), 1.88-1.60 (m, 8H), 1.56-1.29 (m, 7H), 1.24-0.95 (m, 8H), 0.95-0.88 (m, 7H), 0.87-0.55 (m, 4H).

Synthesis of 10.13 To a mixture of MePPh ₃ Br (6.57 g, 18.4 mmol) in THF (40 mL) was added t-BuOK (2.06 g, 18.4 mmol) under N ₂ at 15° C. After stirring at 15° C. for 30 min, 10.12 (800 mg, 2.30 mmol) in THF (10 mL) was added. After stirring at 40° C. for 2 h, the reaction mixture was poured into aqueous NH ₄ Cl (150 mL) and extracted with EtOAc (2×200 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (12-20% EtOAc in PE) to give 10.13 (650 mg, 82.0%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 4.81 (s, 1H), 4.62 (d, J = 1.6 Hz, 1H), 1.90-1.75 (m, 4H), 1.73 (s, 3H), 1.73-1.58 (m, 5H), 1.56-1.20 (m, 8H), 1.12-0.94 (m, 7H), 0.91 (t, J = 7.6 Hz, 4H), 0.87-0.83 (m, 4H), 0.82-0.56 (m, 3H).

Synthesis of 10.14 To a solution of 10.13 (450 mg, 1.30 mmol) in DCM (15 mL) was added m-CPBA (527 mg, 85%, 2.60 mmol). After stirring at 0° C. for 1 h, the mixture was quenched _{with NaHCO} (50 mL, saturated aqueous solution) and Na _{S O} (20 mL, saturated aqueous solution). The organic layer was separated, dried _{over Na} SO , filtered, and concentrated under reduced pressure to give 10.14 (360 mg, 76.9%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.77-2.70 (m, 1H), 2.68-2.61 (m, 1H), 1.87-1.72 (m, 6H), 1.52-1.41 (m, 5H), 1.30-1.23 (m, 9H), 0.94-0.90 (m, 7H), 0.89-0.87 (m, 3H), 0.86-0.59 (m, 8H).

Synthesis of 10 and 11. To a solution of 10.14 (360 mg, 0.998 mmol) in DMF (10 mL) was added 1H-pyrazole-4-carbonitrile (185 mg, 1.99 mmol) and Cs ₂ CO ₃ (648 mg, 1.99 mmol) at 20° C. After stirring at 130° C. for 2 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were separated, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (30-65% EtOAc in PE) to give a mixture of diastereomers 10 and 11 (200 mg, 44.2% yield) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.93 (s, 1H), 7.80 (s, 1H), 4.41-4.35 (m, 1H), 4.27-4.21 (m, 1H), 2.50 (s, 1H), 2.41-2.26 (m, 1H), 1.91-1.72 (m, 8H), 1.53-1.39 (m, 7H), 1.17-1.06 (m, 3H), 1.01 (s, 3H), 0.97 (s, 3H), 0.94-0.89 (m, 5H), 0.87-0.83 (m, 5H), 0.78-0.55 (m, 3H).

The diastereomers were separated by SFC (Column: DAICEL CHIRALCEL OJ-H 250mm*30mm, 5um; Conditions: _0.1 % _NH3H2O EtOH; Gradient: 25% to 25% B; Flow rate: 60mL/min; Column temperature: 40°C) to give 11 (30mg) and 10 (130.5mg) as solids. 11 was re-purified by SFC (Column: DAICEL CHIRALCEL OJ-H 250mm*30mm, 5um; Conditions: _0.1 % _NH3H2O EtOH; Gradient: 20% to 20% B; Flow rate: 60mL/min; Column temperature: 40°C) to give 11 (16.9mg) as a solid.

10: ¹ H NMR (400 MHz, CDCl3) δ _H 7.93 (s, 1H), 7.80 (s, 1H), 4.40-4.35 (m, 1H), 4.26-4.21 (m, 1H), 2.47 (s, 1H), 2.35-2.29 (m, 1H), 1.91-1.59 (m , 9H), 1.53-1.35 (m, 6H), 1.33-1.23 (m, 3H), 1.18-1.03 (m, 3H), 1.01 (s, 3H), 0.99-0.95 (m, 5H), 0.91 (t, J = 7.6 Hz, 4H), 0.87-0.68 (m, 3H), 0.66-0.55 (m, 1H). LC-ELSD/MS purity 99%; MS ESI calculated for C ₂₈ H ₄₀ N ₃ [M-2H ₂ O+H] ⁺ 418.3 found 418.3. SFC: 95% de.

11: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.89 (s, 1H), 7.84 (s, 1H), 4.28 (d, J = 13.6 Hz, 1H), 4.01 (d, J = 13.6 Hz, 1H), 3.00 (s, 1H), 2.41-2.34 (m, 1H), 1.84-1.57 (m, 9H), 1.52-1.40 (m, 6H), 1.19 (s, 3H), 1.10-1.06 (m, 3H) , 1.11-1.05 (m, 1H), 1.02 (s, 3H), 1.01-0.93 (m, 5H), 0.93-0.89 (m, 4H), 0.78-0.66 (m, 3H), 0.62-0.54 (m, 1H). LC-ELSD/MS purity 99%; MS ESI calculated for C ₂₈ H ₄₀ N ₃ [M-2H ₂ O+H] ⁺ 418.3 found 418.3. SFC: 99% de.

Examples 12 and 13: Synthesis of 1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bS,12aS)-8-hydroxy-12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile and 1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bS,12aS)-8-hydroxy-10a,12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile
Synthesis of 12.1 To a solution of freshly prepared MAD (310 mmol) in toluene (300 mL) was added (5β)-androstane-3,17-dione, 12.0 (30 g, 104 mmol) in DCM (100 mL) dropwise at −70° C. After stirring at −70° C. for 1 h under N ₂ , n-PrMgCl 2 (130 mL, 260 mmol, 2 M) was added dropwise at −70° C. After stirring at −70° C. for 4 h, the reaction mixture was poured into saturated aqueous citric acid (1000 mL) at 10° C. and extracted with EtOAc (2×1000 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-30% EtOAc in PE) to give 12.1 (16 g, 47.7%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.49-2.38 (m, 1H), 2.17-2.00 (m, 1H), 1.98-1.76 (m, 4H), 1.74-1.66 (m, 1H), 1.62-1.40 (m, 10H), 1.38-1.15 (m, 9H), 1.12-0.99 (m, 1H), 0.98-0.90 (m, 6H), 0.84 (s, 3H).

Synthesis of 12.2: To a solution of freshly prepared LDA (150 mmol) in THF (100 mL) was added a solution of 12.1 (10 g, 30.0 mmol) and ethyl diazoacetate (19.0 g, 150 mmol, 90%) in THF (200 mL) at −70° C. After stirring at −70° C. for 2 h, the reaction was quenched with acetic acid (8.57 mL, 150 mmol) in THF (20 mL). After warming to room temperature overnight, the reaction was diluted with water (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give 12.2 (13 g, 97.7%) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 4.75-4.65 (m, 1H), 4.25 (q, J=7.2 Hz, 2H), 2.20-2.09 (m, 1H), 1.93-1.76 (m, 3H), 1.72-1.35 (m, 14H), 1.34-1.24 (m, 7H), 1.23-0.99 (m, 5H), 0.96-0.91 (m, 6H), 0.89 (s, 3H).

Synthesis of 12.3 To a solution of 12.2 (13 g, 29.1 mmol) in DME (130 mL) was added _Rh2 (OAc) ₄ (300 mg, 0.6787 mmol) in one portion at 15°C. After stirring at 15°C for 16 h, the reaction was diluted with water (300 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (300 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated to give 12.3 (11 g, 90.9%) as an oil.

Synthesis of 12.4 To a solution of 12.3 (11 g, 26.2 mmol) in MeOH (110 mL) was added KOH (14.6 g, 262 mmol) at 20° C. After stirring at 70° C. for 3 h, the reaction mixture was added to saturated brine (100 mL) and extracted with DCM (2×200 mL). The combined organic layers were washed with HCl (200 mL, 1 N), saturated NaHCO ₃ (200 mL), saturated brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give 12.4 (11 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.61 (dt, J=6.8, 14.0 Hz, 1H), 2.24-2.15 (m, 1H), 2.09-2.01 (m, 1H), 1.91-1.68 (m, 6H), 1.67-1.43 (m, 10H), 1.42-1.19 (m, 10H), 1.06 (s, 3H), 0.96-0.90 (m, 6H).

Synthesis of 12.5 To a mixture of EtPPh ₃ Br (38.2 g, 103 mmol) in THF (160 mL) was added t-BuOK (11.5 g, 103 mmol) at 20° C. under N ₂ . After stirring at 40° C. for 30 min, 12.4 (9.0 g, 25.9 mmol) was added at 40° C. After stirring at 40° C. for 16 h, the reaction mixture was quenched with saturated aqueous NH ₄ Cl (150 mL) at 20° C. and extracted with EtOAc (2×100 mL). The combined organic phases were concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give 12.5 (4.2 g, 45.2%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δH 5.25-5.05 (m, 1H), 2.54-2.10 (m, 1H), 1.99-1.69 (m, 7H), 1.67-1.57 (m, 4H), 1.54-1.20 (m, 16H), 1.05-0.98 (m, 4H), 0.96-0.86 (m, 9H).

Synthesis of 12.6 To _a solution of 12.5 (4.2 g, 11.7 mmol) in THF (40 mL) was added _BH3.Me2S (3.51 mL, 10 M, 35.1 mmol). After stirring at 15°C for 16 h, the reaction was treated sequentially with EtOH (6.73 mL, 117 mmol), dropwise NaOH (4.67 g, 5 M, 117 mmol in 23.4 _mL of water), and dropwise _H2O2 (11.7 mL, 10 M, 117 mmol) at 0°C. After stirring at ₇₀ °C for 2 h, the mixture was quenched with _Na2SO3 (100 mL, 10%) and extracted with EtOAc (2 x 100 mL). The combined organic layers were separated, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give 12.6 (4.2 g) as a solid that was used as is.

Synthesis of 12.7 To a solution of 12.6 (4.2 g, 11.1 mmol) in DCM (50 mL) was added DMP (9.41 g, 22.2 mmol). After stirring at 20° C. for 1 h, the mixture was quenched with NaHCO ₃ (100 mL, saturated) and Na ₂ S ₂ O ₃ (100 mL, saturated). The organic layer was separated, dried over Na ₂ SO ₄ , filtered, and concentrated to give 12.7 (4.0 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.50-2.24 (m, 1H), 2.16-2.10 (m, 3H), 1.93-1.64 (m, 7H), 1.54-1.43 (m, 6H), 1.39-1.12 (m, 11H), 1.05-0.82 (m, 14H).

Synthesis of 12.8 To a solution of 12.7 (3.5 g, 9.34 mmol) in MeOH (80 mL) was added MeONa (10.0 g, 186 mmol) at 0° C. After stirring at 80° C. for 16 h, the reaction mixture was concentrated. The residue was diluted with saturated NH ₄ Cl (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 12.8 (2.2 g, 63.0%) as a solid. ^1H NMR (400 MHz, _CDCl3 ) 2.32-2.25 (m, 1H), 2.13 (s, 3H), 1.89-1.75 (m, 3H), 1.74-1.56 (m, 5H), 1.52-1.40 (m, 6H), 1.39-1.17 (m, 10H), 1.04-0.96 (m, 2H), 0.95-0.92 (m, 4H), 0.91-0.89 (m, 6H), 0.89-0.82 (m, 1H); LC-ELSD/MS: Purity >99%, C MS ESI calculated for _{25H 41} O[M-H2O+H] ⁺ 357.3, found 357.3.

Synthesis of 12.9 To a mixture of MePPh ₃ Br (3.78 g, 10.6 mmol) in THF (16 mL) was added t-BuOK (1.18 g, 10.6 mmol) at 20° C. under N ₂ . After stirring at 50° C. for 30 min, 12.8 (1.0 g, 2.66 mmol) was added at 50° C. After stirring at 50° C. for 16 h, the reaction mixture was quenched with saturated aqueous NH ₄ Cl (150 mL) at 20° C. and extracted with EtOAc (2×100 mL). The combined organic phases were concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give 12.9 (700 mg, 70.6%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 4.80 (s, 1H), 4.60 (d, J=2.0 Hz, 1H), 1.87-1.58 (m, 12H), 1.54-1.23 (m, 17H), 1.12-0.97 (m, 3H), 0.96-0.91 (m, 4H), 0.90 (s, 3H), 0.80 (s, 3H).

Synthesis of 12.10 To a solution of 12.9 (700 mg, 1.87 mmol) in DCM (10 mL) was added m-CPBA (758 mg, 3.74 mmol). After stirring at 20° C. for 1 h, the mixture was quenched with _NaHCO (20 _mL , saturated) and Na _{S O} (20 mL, saturated). The organic layer was separated, dried _{over Na} SO , filtered, and concentrated to give 12.10 (700 mg) as a solid, which was used as is.

Synthesis of 12 and 13. To a solution of 12.10 (400 mg, 1.02 mmol) in DMF (20 mL) was added 1H-pyrazole-4-carbonitrile (189 mg, 2.04 mmol) and Cs ₂ CO ₃ (668 mg, 2.04 mmol) at 20° C. After stirring at 120° C. for 48 h, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column (5-40% EtOAc in PE) to give a mixture of diastereomers 12 and 13 (350 mg, 71.2%) as a solid. 12 and 13 (350 mg, 0.7 mmol) were separated by SFC (Column: DAICEL CHIRALCEL OJ-H (250 mm * 30 mm * 5 um); Mobile phase: A: CO ₂ B: 0.1% NH ₃ H ₂ O EtOH; Gradient: 20% to 20% B, Flow rate (ml/min): 60) to give both 12 (41.0 mg, 11.7%) and 13 (98.4 mg, 28.1%) as solids.

12: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.88 (s, 1H), 7.87 (s, 1H), 4.33-3.94 (m, 2H), 3.06 (s, 1H), 2.45-2.35 (m, 1H), 1.87-1.61 (m, 5H), 1.52-1.20 (m, 15H), 1.18 (s, 3H), 1.13-1.01 (m, 3H), 0.98 (s, 3H), 0.93 (t, J=7.2 Hz, 4H), 0.87 (s, 3H), 0.85-0.66 (m, 3H). LC-ELSD/MS: Purity >99%, analytical SFC: 97.84% de; MS ESI calculated for C ₃₀ H ₄₄ N ₃ [M-2H ₂ O+H] ⁺ 446.4, found 446.4.

13: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.91 (s, 1H), 7.79 (s, 1H), 4.39-4.19 (m, 2H), 2.40 (s, 1H), 2.36-2.29 (m, 1H), 1.91-1.63 (m, 7H), 1.53-1.41 (m, 7H) ), 1.40-1.10 (m, 13H), 0.98 (s, 3H), 0.96-0.91 (m, 7H), 0.90-0.85 (m, 4H); LC-ELSD/MS: purity >99%, analytical SFC: 99.64%, C MS for ₃₀ H ₄₄ N ₃ [M-2H ₂ O+H] ⁺ Calculated ESI value: 446.4, measured value: 446.4.

Examples 14 and 15: Synthesis of 1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile and 1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile
Synthesis of 14.1 To a solution of freshly prepared MAD (519 mmol) in toluene (1 L) was added dropwise a solution of 12.0 (50.0 g, 173 mmol) in DCM (200 mL) at −70° C. After stirring at −70° C. for 1 h under N ₂ , MeMgBr (173 mL, 519 mmol, 3 M in ethyl ether) was added dropwise at −70° C. After stirring at −70° C. for 2 h, the reaction mixture was poured into saturated aqueous citric acid (1000 mL) at 10° C. and extracted with EtOAc (2×400 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc = 10/1 to 3/1) to give 14.1 (36 g, 68%) as a solid. ¹ HNMR (400 MHz, CDCl ₃ ) δ _H 2.48-2.38 (m, 1H), 2.13-2.02 (m, 1H), 1.98-1.85 (m, 3H), 1.83-1.69 (m, 2H), 1.63-1.43 (m, 8H), 1.39-1.14 (m, 10H), 1.12-1.02 (m, 1H), 0.97 (s, 3H), 0.84 (s, 3H).

Synthesis of 14.2: To a solution of freshly prepared LDA (82.1 mmol) in THF (100 mL) was added a solution of 14.1 (6 g, 19.7 mmol) and ethyl diazoacetate (12.4 g, 98.4 mmol, 90%) in THF (120 mL) at −70° C. After stirring at −70° C. for 2 h, the reaction was quenched with acetic acid (5.61 mL, 98.4 mmol) in THF (15 mL), warmed to 20° C. for 16 h, diluted with water (300 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-15% EtOAc in PE) to give 14.2 (8.0 g, 97%) as an oil. ¹ HNMR (400 MHz, CDCl ₃ ) δ _H 4.69 (br s, 1H), 4.25 (q, J = 7.2 Hz, 2H), 2.18-2.08 (m, 1H), 2.04 (s, 1H), 2.01-1.93 (m, 1H), 1.91-1.78 (m, 2H), 1.76-1.63 (m, 2H), 1.60-1.38 (m, 9H), 1.35-1.29 (m, 4H), 1.28-1.23 (m, 5H), 1.14-0.98 (m, 4H), 0.94 (s, 3H), 0.89 (s, 3H).

Synthesis of 14.3 To a solution of 14.2 (8.0 g) in DME (100 mL) was added _Rh2 (OAc) ₄ (211 mg, 0.48 mmol) in one portion at 15°C. After stirring at 30°C for 12 h, the mixture was diluted with _H2O (100 mL) and extracted with EtOAc (3 x 60 mL). The combined organic phases were washed with brine (2 x 30 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated to give 14.3 (7.7 g) as an oil. ¹ HNMR (400 MHz, CDCl ₃ ) δ _H 12.41 (s, 1H), 4.24-4.15 (m, 2H), 3.74-2.27 (m, 2H), 2.22-2.11 (m, 1H), 1.98-1.69 (m, 5H), 1.57-1.35 (m, 8H), 1.32-1.24 (m, 9H), 1.22-1.01 (m, 7H), 0.96-0.90 (m, 3H).

Synthesis of 14.4 To a solution of 14.3 (7.7 g, 19.7 mmol) in MeOH (100 mL) was added KOH (6.62 g, 118 mmol) at 15° C. After stirring at 70° C. for 1 h, the reaction mixture was poured into saturated brine (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with HCl (1 M, 100 mL), saturated NaHCO ₃ (100 mL), brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 14.4 (5.8 g, 93%) as a solid. ¹ HNMR (400 MHz, CDCl ₃ ) δ _H 2.66-2.55 (m, 1H), 2.23-2.16 (m, 1H), 2.09-2.01 (m, 1H), 1.93-1.84 (m, 2H), 1.83-1.72 (m, 3H), 1.67-1.50 (m, 6H), 1.44-1.31 (m, 5H), 1.30-1.13 (m, 7H), 1.09-0.99 (m, 5H), 0.93 (s, 3H).

Synthesis of 14.5 To a mixture of _Ph3PEtBr (40.4 g, 109 mmol) in THF (160 mL) was added t-BuOK (12.2 g, 21.8 mmol) at 20 °C under _N2 . After stirring at 40 °C for 1 h, 14.4 (5.8 g, 18.2 mmol) was concentrated. After stirring at 40 °C for ₂ h, the reaction mixture was quenched at 20 °C with 10% aqueous _NH4Cl (60 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous _Na2SO4 , filtered, and concentrated. The residue was purified by flash column (0-15% EtOAc in PE) to give 14.5 (5.3 g, 88%) as an oil. ¹ HNMR (400 MHz, CDCl ₃ ) δ _H 5.20-5.09 (m, 1H), 2.55-2.10 (m, 2H), 2.01-1.70 (m, 7H), 1.66-1.58 (m, 3H), 1.53-1.31 (m, 7H), 1.31-1.22 (m, 6H), 1.22-1.01 (m, 5H), 1.00-0.82 (m, 7H).

Synthesis of 14.6 To _a solution of 14.5 (5.3 g, 16 mmol) in THF (80 mL) was added _BH3.Me2S (4.8 mL, 48 mmol, 10 M) under _N2 . After stirring at 20 °C for 12 h under _N2 , the mixture was cooled to 0 °C, and EtOH (16.5 mL, 288 mmol) and NaOH (57.6 _mL , 5 M, 288 mol) were added. _H2O2 (28.8 mL, 10 M, 288 mmol) was then added dropwise. After stirring at 70 °C for 2 h, the mixture was cooled, poured into _Na2S2O3 ( _{500 mL} , saturated), stirred for 30 min, and extracted with EtOAc (2 x 200 mL). The combined organic phases were washed with saturated brine (2 x 100 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated to give 14.6 (5.57 g) as a solid. ^1H NMR (400 MHz, _CDCl3 ) _δH 1.97-1.72 (m, 5H), 1.70-1.67 (m, 1H), 1.55-1.34 (m, 8H), 1.31-1.18 (m, 12H), 1.17-0.99 (m, 5H), 0.97-0.85 (m, 8H), 0.79-0.72 (m, 1H).

Synthesis of 14.7 To a solution of 14.6 (5.57 g, 15.9 mmol) in DCM (120 mL) was added DMP (13.4 g, 31.8 mmol) at 20° C. After stirring at 20° C. for 1 h, the mixture was quenched with saturated aqueous NaHCO ₃ (100 mL). The DCM phase was separated and washed with saturated aqueous NaHCO ₃ /Na ₂ S ₂ O ₃ (1:1, 2×100 mL), brine (30 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give 14.7 (4.95 g, 90%) as an oil. ¹ HNMR (400 MHz, CDCl ₃ ) δ _H 2.48-2.25 (m, 1H), 2.13 (d, J = 1.6 Hz, 3H), 1.98-1.87 (m, 1H), 1.86-1.65 (m, 5H), 1.63-1.43 (m, 8H), 1.42-1.28 (m, 5H), 1.24-1.14 (m, 5H), 1.08-0.92 (m, 3H), 0.91-0.83 (m, 7H).

Synthesis of 14.8 To a solution of 14.7 (4.95 g, 14.2 mmol) in MeOH (80 mL) was added MeONa (15.2 g, 283 mmol) in one portion under _N2 . After stirring at 80 °C for 48 h, the mixture was diluted with _H2O (60 mL) and extracted with EtOAc (3 x 70 mL). The combined organic phases were washed with brine (50 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated to give 14.8 (3.9 g) as a solid. ¹ HNMR (400 MHz, CDCl ₃ ) δ _H 2.32-2.24 (m, 1H), 2.13 (s, 3H), 1.97-1.89 (m, 1H), 1.87-1.66 (m, 5H), 1.57-1.32 (m, 9H), 1.31-1.17 (m, 9H), 1.07-0.93 (m, 3H), 0.91-0.86 (m, 7H).

Synthesis of 14.9 To a mixture of MePPh ₃ Br (12.3 g, 34.6 mmol) in THF (50 mL) was added t-BuOK (3.87 g, 34.9 mmol) under N ₂ at 20° C. After stirring at 50° C. for 1 h, 14.8 (2.0 g, 5.8 mmol) was added at 50° C. After stirring at 50° C. for 12 h, the reaction mixture was quenched with 10% aqueous NH ₄ Cl (100 mL) at 20° C. and extracted with EtOAc (2×80 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-10% EtOAc in PE) to give 14.9 (1.6 g, 81%) as an oil. ¹ HNMR (400 MHz, CDCl ₃ ) δ _H 4.80 (s, 1H), 4.60 (s, 1H), 1.98-1.89 (m, 1H), 1.86-1.74 (m, 3H), 1.69-1.55 (m, 5H), 1.54-1.47 (m, 3H), 1.47-1.36 (m, 5H), 1.30-1.24 (m, 6H), 1.17-0.92 (m, 6H), 0.90 (s, 3H), 0.89-0.84 (m, 3H), 0.80 (s, 3H).

Synthesis of 14.10 To a solution of 14.9 (1.5 g, 4.4 mmol) in DCM (30 mL) was added m-CPBA (1.76 g, 8.7 mmol, 85% purity) under _N at 25°C. After stirring at 25°C for 4 h, the mixture was quenched with saturated aqueous NaHCO ( ₂₀ mL) and extracted with DCM (3 x 30 _mL ). The combined organic solution was washed with saturated aqueous _NaHCO /Na _SO (1: ₁ , 30 mL), brine (20 mL), dried _{over Na} SO , filtered, and concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give 14.10 (1.52 g, 97%) as a solid. ¹ HNMR (400 MHz, CDCl ₃ ) δ _H 2.73-2.62 (m, 2H), 1.87-1.72 (m, 5H), 1.68-1.58 (m, 5H), 1.50-1.30 (m, 8H), 1.25 (s, 3H), 1.22 (s, 3H), 1.07-0.96 (m, 2H), 0.93-0.88 (m, 8H), 0.87-0.71 (m, 4H).

Synthesis of 14 and 15. To a solution of 14.10 (1.52 g, 4.2 mmol) in DMF (30 mL) was added 1H-pyrazole-4-carbonitrile (587 mg, 6.3 mmol) and Cs ₂ CO ₃ (4.10 g, 12.6 mmol) under N ₂ . After stirring at 130 °C for 72 h, the mixture was diluted with H ₂ O (40 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with H ₂ O (4 × 50 mL) and brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-35% EtOAc in PE) to give a mixture of diastereomers 14 and 15 (0.85 g) as a solid. ¹ HNMR (400 MHz, CDCl ₃ ) δ _H 7.94-7.88 (m, 1H), 7.81-7.77 (m, 1H), 4.38-4.27 (m, 1H), 4.26-4.19 (m, 1H), 2.36-2.28 (m, 1H), 1.97-1.82 (m, 3H), 1.78-1.74 (m, 2H), 1.74-1.65 (m, 4H), 1.64-1.56 (m, 2H), 1.55-1.32 (m, 10H), 1.31-1.28 (m, 1H), 1.20-1.01 (m, 4H), 0.99-0.93 (m, 7H), 0.91-0.85 (m, 5H).

Diastereomers 14 and 15 (0.81 g) were separated by SFC (Column: DAICEL CHIRALCEL OD-H (250 mm * 30 mm * 5 um), A: CO ₂ ; B: 0.1% NH ₃ H ₂ O EtOH; Gradient: 30-30%, Flow rate: 50 mL/min) to give both 14 (112 mg) and 15 (351.4 mg) as solids.

14: ¹ HNMR (400 MHz, _CDCl3 ) _δH 7.89-7.87 (m, 1H), 7.87-7.86 (m, 1H), 4.33-4.23 (m, 1H), 4.03-3.90 (m, 1H), 3.07 (s , 1H), 2.44-2.36 (m, 1H), 1.95-1.86 (m, 1H), 1.84-1.65 (m, 4H), 1.51-1.44 (m, 3H), 1 ．． 43-1.34 (m, 5H), 1.29-1.20 (m, 6H), 1.20-1.16 (m, 4H), 1.07-0.99 (m, 2H), 0.99-0.8 9 (m, 5H), 0.89-0.83 (m, 4H), 0.83-0.66 (m, 3H); LC-ELSD/MS: purity 99%, analytical SFC: 99.74% de; MS ESI calculated value for C ₂₈ H ₄₀ N ₃ [M-2H ₂ O+H] ⁺ 418.3, observed value 418.3.

15: ¹ HNMR (400 MHz, _CDCl3 ) _δH 7.91 (s, 1H), 7.79 (s, 1H), 4.38-4.30 (m, 1H), 4.26-4.19 (m, 1H), 2.41 (s, 1H), 2.37-2.30 (m, 1H), 1.97-1.71 (m, 6H), 1.66- 1.59 (m, 1H), 1.55-1.35 (m, 9H), 1.30-1.13 (m, 8H), 1.08-0.94 (m, 8H), 0.93-0.85 (m, 5H); LC-ELSD/MS: purity 99%, analytical SFC: 100% de; C ₂₈ H ₄₀ N ₃ MS ESI calculated for [M-2H ₂ O+H] ⁺ 418.3, found 418.3.

Examples 16 and 17: Synthesis of 1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aS,8R,10aS,10bS,12aS)-8-hydroxy-12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile and 1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aS,8R,10aS,10bS,12aS)-8-hydroxy-10a,12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile
Synthesis of 16.2 To a mixture of (3α,5α)3-hydroxy-androstan-17-one, 16.1 (10 g, 34.4 mmol) in THF (100 mL) was added LDA (1 M, 160 mL, 160 mmol) at −70°C under _N. After stirring at −70°C for 2 h, the reaction mixture was quenched with HOAc (10.2 g, 171 mmol) in THF (100 mL) at 0°C. After slowly warming to room temperature overnight, the reaction was diluted with water (400 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (300 mL), dried _over anhydrous _NaSO , and evaporated under reduced pressure to give 16.2 (15 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 0.82 (s, 3H), 0.91 (s, 3H), 0.95-1.01 (m, 1H), 1.05-1.15 (m, 2H), 1.26-1.33 (m, 6H), 1.35-1.52 (m, 6H), 1.54-1.73 (m, 6H), 1.74-1.92 (m, 4H), 2.11-2.22 (m, 1H), 3.55-2.60 (m, 1H), 4.20-4.28 (m, 2H), 4.69 (s, 1H).

Synthesis of 16.3 To a solution of 16.2 (10 g, 24.7 mmol) and DME (200 mL) was added _Rh2 (OAc) ₄ (196 mg, 0.4445 mmol) in one portion at 15° C. After stirring under _N2 at 15° C. for 16 h, the reaction mixture was concentrated to give 16.3 (10.5 g) as a solid, which was used directly in the next step without purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 0.65-0.88 (m, 4H), 0.93-1.12 (m, 7H), 1.21-1.38 (m, 7H), 1.37-1.28 (m, 6H), 1.64-1.88 (m, 5H), 1.91-2.36 (m, 4H), 3.51-3.63 (m, 1H), 4.12-4.26 (m, 2H).

Synthesis of 16.4 To a solution of NaOH (2.64 g, 66.0 mmol) in H ₂ O (20 mL) was added 16.3 (5 g, 13.2 mmol) in MeOH (100 mL)/THF (30 mL). After stirring at 60° C. for 16 hours, the reaction mixture was poured into H ₂ O (100 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with HCl (1 M, 100 mL), saturated NaHCO ₃ (100 mL), brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by trituration with EtOAc/PE (3:1, 100 mL) at 15° C. to give 16.4 (2.5 g, 50%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 0.62-0.65 (m, 1H), 0.79 (s, 3H), 1.08 (s, 3H), 1.24-1.38 (m, 6H), 1.41-1.63 (m, 9H), 1.72-1.85 (m, 6H), 2.02-2.08 (m, 1H), 2.16-2.25 (m, 1H), 2.58-2.66 (m, 1H), 3.52-3.63 (m, 1H).

Synthesis of 16.5: To a suspension of _Ph3PEtBr (29.1 g, 78.6 mmol) in anhydrous THF (25 mL) was added t-BuOK (8.8 g, 78.6 mmol) under _N2 at 25 °C. After stirring at 45 °C for 30 min, a solution of 16.4 (4 g, 13.1 mmol) in anhydrous THF (25 mL) was added dropwise. After stirring for 12 h, the reaction mixture was combined with another batch prepared from 4 g of 16.4. The combined mixture was cooled, poured into ice-water (600 mL), and stirred for 10 min. The aqueous phase was extracted with EtOAc (2 × 400 mL). The combined organic phase was washed with brine (2 × 400 mL), filtered, and concentrated. The residue was purified by flash column (0-30% EtOAc in PE) to give 16.5 (9 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 0.57-0.72 (m, 1H), 0.57-0.73 (m, 1H), 0.77-0.80 (m, 3H), 0.90-0.96 (m, 3H), 0.97-1.01 (m, 1H), 1.03-1.09 (m, 3H), 1.16-1.42 (m, 6H), 1.53-1.62 (m, 5H), 1.66-1.75 (m, 4H), 1.80-1.90 (m, 3H), 1.92-2.04 (m, 1H), 2.11-2.33 (m, 2H), 2.45-2.54 (m, 1H), 3.44-3.66 (m, 1H), 5.08-5.23 (m, 1H).

Synthesis of 16.6 To a solution of 16.5 (9 g, 28.4 mmol) in DCM (100 mL) was added DMP (24 g, 56.8 mmol). After stirring at 25 °C for 2 hours, the mixture was quenched with saturated aqueous NaHCO ₃ (50 mL) at 10 °C. The DCM phase was separated and washed with saturated aqueous NaHCO ₃ /Na ₂ S ₂ O ₃ (1:1, 2 × 100 mL), brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified with MeCN (210 mL) at 82 °C to give 16.6 (8 g, 89.5%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.69-0.92 (m, 3H), 0.94 (s, 1H), 0.97-1.01 (m, 3H), 1.05-1.19 (m, 4H), 1.31-1.48 (m, 5H), 1.55-1.61 (m, 2H), 1.64-1.76 (m, 3H), 1.80-2.12 (m, 5H), 2.13-2.46 (m, 4H), 2.46-2.55 (m, 1H), 2.82 (dd, J = 16.44, 2.13 Hz, 1H), 3.27 (br d, J = 16.56 Hz, 1H), 5.10-5.24 (m, 1H).

Synthesis of 16.7 To a stirred solution of trimethylsulfoxonium iodide (11.1 g, 50.8 mmol) in DMSO (100 mL) was added t-BuOK (7.12 g, 63.5 mmol). After stirring at 25°C for 1.0 h under _N2 , 16.6 (8 g, 25.4 mmol) was added. After stirring at 60°C for 12 h, the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with water (2 x 100 mL), brine (30 _mL ), dried over _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by flash column (PE/EtOAc = 0-30%) to give 16.7 (4 g, 47.9%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 0.81-0.84 (m, 4H), 0.93 (s, 2H), 0.95-0.98 (m, 1H), 1.03-1.07 (m, 2H), 1.22-1.38 (m, 8H), 1.38-1.46 (m, 2H), 1.62-1.69 (m, 2H), 1.70-1.78 (m, 4H), 1.79-1.94 (m, 4H), 1.98-2.09 (m, 2H), 2.11-2.23 (m, 1H), 2.46-2.54 (m, 1H), 2.59-2.64 (m, 2H), 5.11-5.21 (m, 1H).

Synthesis of 16.8 To a solution of 16.7 (4 g, 12.1 mmol) in THF (50 mL) was added CuI (1.15 g, 6.05 mmol) followed by EtMgBr (12.1 mL, 3 M, 36.3 mmol) at 0 °C. After stirring at 0 °C for 1 h, the mixture was poured into water (200 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with brine (200 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated to give 16.8 (3.2 g, 73.9%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 0.69-0.74 (m, 3H), 0.77-0.83 (m, 1H), 0.87-0.95 (m, 5H), 1.02-1.17 (m, 5H), 1.18-1.32 (m, 8H), 1.38 (br d, J = 3.26 Hz, 4H), 1.48-1.54 (m, 1H), 1.58 (br t, J = 2.64 Hz, 5H), 1.62-1.70 (m, 3H), 1.71-1.77 (m, 2H), 1.79-1.94 (m, 2H), 2.10-2.26 (m, 1H), 2.49 (br d, J = 14.05 Hz, 1H), 5.10-5.20 (m, 1H).

Synthesis of 16.9 To a solution of 16.8 (3.2 g, 8.92 mmol) in THF (30 mL) was added _BH3.Me2S (2.67 mL, 26.7 mmol) at 25°C. After stirring at ₄₅ °C for 2 h, the reaction mixture was cooled and quenched with EtOH (4.10 g, 89.2 mmol, 0.789 g/mL) at 0°C, followed by the slow addition of _NaOH (1.78 mL, 5 M, 8.92 mmol) _H2O2 (10.1 g, 89.2 mmol, 1.13 g/mL, 30% in water) until the internal temperature no longer rose, maintaining the internal temperature below 30°C. After stirring at ₆₀ °C for 1 h, the reaction was quenched with saturated _{aqueous Na2S2O3} (100 mL) and stirred at 0°C for 1 h. The reaction was checked by potassium iodide-starch test paper to ensure excess H ₂ O ₂ was destroyed (no blue color change). The aqueous phase was extracted with DCM (3 × 100 mL). The combined organic phases were washed with saturated Na ₂ S ₂ O ₃ (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 16.9 (3.5 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 0.61-0.66 (m, 3H), 0.70 (s, 1H), 0.68-0.72 (m, 1H), 0.72-0.78 (m, 2H), 0.81-0.89 (m, 5H), 0.90 (s, 1H), 0.93-1.01 (m, 1H), 1.03 (d, J = 6.27 Hz, 1H), 1.09 (br d, J = 6.53 Hz, 2H), 1.13-1.25 (m, 9H), 1.26 (br s, 1H), 1.31 (br d, J = 3.01 Hz, 4H), 1.39 (br d, J = 3.76 Hz, 2H), 1.45 (br d, J = 11.29 Hz, 2H), 1.47-1.64 (m, 6H), 1.71-1.87 (m, 2H), 2.55 (s, 1H).

Synthesis of 16.10 To a solution of 16.9 (3.5 g, 9.29 mmol) in DCM (100 mL) was added silica gel (3.98 g) and PCC (3.98 g, 18.5 mmol) at 25 °C. After stirring at 25 °C for 2 hours, the resulting mixture was filtered through a silica gel pad, and the filter cake was washed with DCM (40 mL × 5). The combined filtrate was concentrated to give 16.10 (2.5 g, 71.8%) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 0.63 (d, J = 1.00 Hz, 3H), 0.69-0.81 (m, 3H), 0.85 (br d, J = 0.75 Hz, 6H), 1.01-1.11 (m, 2H), 1.19 (t, J = 7.15 Hz, 5H), 1.29-1.33 (m, 4H), 1.35-1.49 (m, 7H), 1.54 (s, 3H), 1.56-1.81 (m, 4H), 2.06 (d, J = 5.27 Hz, 3H), 2.22 (dd, J = 12.80, 3.26 Hz, 1H), 2.39 (d, J = 5.27 Hz, 1H).

Synthesis of 16.10a and 16.10b To a solution of 16.10 (250 mg, 0.667 mmol) in MeOH (10 mL, 0.667 mmol) was added sodium methoxide (718 mg, 13.3 mmol) in one portion. After stirring at 70°C for 12 hours, the mixture was cooled and concentrated under reduced pressure at 25°C. The residue was poured into ice water (20 mL) and stirred for 20 minutes. The aqueous phase was extracted with EtOAc (3 x 40 mL). The combined organic phase was washed with brine (2 x 20 _mL ), dried over anhydrous _Na2SO4 , filtered, and concentrated. The residue was purified by preparative HPLC (Column: Welch Xtimate C18 150*25 mm*5 um; Conditions: water (0.225% FA)-ACN; Start B: 80%; End B: 100%) to give 16.10a (22 mg, 8.8%) and 16.10b (6.1 mg, 2.44%) as solids.

16.10: ¹ H NMR (400 MHz, CDaCl ₃ ) δ _H 0.72 (s, 3H), 0.76-0.88 (m, 3H), 0.90-1.01 (m, 7H), 1.13-1.20 (m, 1H), 1.22 (br d, J = 4.02 Hz, 1H), 1.23-1.26 (m, 3H), 1.28 (br s, 1H), 1.29-1.33 (m, 2H), 1.38-1.44 (m, 5H), 1.45-1.62 (m, 9H), 1.65-1.79 (m, 1H), 1.80-1.90 (m, 2H), 2.16 (s, 3H), 2.31 (dd, J = 12.67, 3.14 Hz, 1H), . LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₅ H ₄₁ O ₁ [MH ₂ O+H] ⁺ 357.3 found 357.3.

16.10b: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 0.67-0.72 (m, 4H), 0.78-0.86 (m, 2H), 0.88-0.95 (m, 8H), 1.08-1.16 (m, 2H), 1.17-1.24 (m, 5H), 1.24-1.31 (m, 5H), 1.36-1.38 (m, 4H), 1.41-1.46 (m, 4H), 1.51 (br d, J = 3.76 Hz, 2H), 1.66-1.88 (m, 2H), 2.12 (s, _{3H), 2.46 (d, J = 5.27 Hz, 1H),. LC-ELSD/MS purity 98%, MS ESI calculated for C25H41O1 [ M} - _H2O +H] ⁺ 357.3 found 357.3.

Synthesis of 16.11 To a stirred solution of trimethylsulfanium (108 mg, 0.532 mmol) in DMSO (5 mL) was added NaH (21.1 mg, 0.532 mmol) at 25 °C. After stirring _{under N} for 1.0 h, 16.10a (100 mg, 0.266 mmol) was added. After stirring at 60 °C for 12 h, the mixture was poured into water (10 mL), stirred for 20 min, and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (2 × 10 mL), dried _over anhydrous _Na SO , filtered, and concentrated to give 16.11 (180 mg) as an oil. The residue was purified by flash column (0-30% EtOAc in PE) to give 16.12 (60 mg) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 0.71 (s, 3H), 0.74-0.84 (m, 4H), 0.85-0.97 (m, 8H), 1.13 (br d, J = 12.55 Hz, 3H), 1.22 (s, 5H), 1.27-1.34 (m, 3H), 1.38 (br d, J = 3.51 Hz, 4H), 1.41-1.53 (m, 5H), 1.59-1.69 (m, 1H), 1.73 (br d, J = 12.55 Hz, 1H), 1.70-1.77 (m, 1H), 1.82 (br s, 2H), 1.91-1.98 (m, 1H), 2.37 (s, 1H), 2.63 (d, J = 4.77 Hz, 1H), 2.70-2.73 (m, 1H).

Synthesis of 16 and 17. To a solution of 16.11 (60 mg, 0.154 mmol) in DMF (3 mL) was added 1H-pyrazole-4-carbonitrile (28.6 mg, 0.308 mmol) and Cs ₂ CO ₃ (100 mg, 0.308 mmol) at 20° C. After stirring at 130° C. for 12 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was separated and concentrated to give a mixture of diastereomers 16 and 17 (30 mg) as a solid. The diastereomers were separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); conditions: 0.1% NH ₃ H ₂ O IPA; start B: 60%; end B: 60%) to give 16 (5.1 mg, 17.0%) and 17 (2.6 mg, 8.369%) as solids.

16: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 0.68 (s, 3H), 0.73-0.94 (m, 7H), 0.99 (s, 3H), 1.06-1.28 (m, 14H), 1.35-1.52 (m, 11H), 1.66 (br d, J = 16.06 Hz, 1H), 1.80 (br t, J = 13.80 Hz, 2H), 2.37 (br d, J = 12.05 Hz, 1H), 2.98 (s, 1H), 3.92-4.32 (m, 2H), 7.86 (d, J = 19.58 Hz, 2H),. LC-ELSD/MS purity 99%, MS ESI calculated for C ₃₀ H ₄₄ N ₃ [M-2H ₂ O+H] ⁺ 446.4, found 446.4. SFC 100% de.

17: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 0.63 (s, 3H), 0.69-0.86 (m, 7H), 0.88 (s, 3H), 0.92 (s, 3H), 1.01-1.24 (m, 11H), 1.27-1.42 (m, 10H), 1.61-1.84 (m, 4H), 2.25 (br d, J = 12.55 Hz, 1H), 2.38 (s, 1H), 4.11-4.34 (m, 2H), 7.64-7.91 (m, 2H),. LC-ELSD/MS purity 99%, MS ESI calculated for C ₃₀ H ₄₄ N ₃ [M-2H ₂ O+H] ⁺ 446.3 found 446.3.

Examples 18 and 19: 1-((S)-2-hydroxy-2-((1S,3aS,3bS,8S,10aR,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyl-1,2,3,3a,3b,4,6,7,8,9,10,10a,10b,11,12,12a-hexadecahydrocyclohepta[a]cyclopenta[f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (18) and 1-((R)-2-hydroxy-2-((1S,3aS,3bS,8S,10aR,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyl-1,2,3,3a,3b,4,6,7,8,9,10,10a,10b,11,12,12a-hexadecahydrocyclohepta[a]cyclopenta[f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (19).
Synthesis of 18.2: To a solution of 18.1 (50.0 g, 157 mmol) in toluene (500 mL) was added pyridine HCl (3.61 g, 31.4 mmol) and ethane-1,2-diol (48.7 g, 785 mmol). The mixture was stirred at 135° C. for 48 hours, and water was removed by a Dean-Stark trap. The mixture was concentrated under reduced pressure. The residue was triturated with EtOAc (150 mL) to give product 18.2 (35.0 g, 62%). ^1H NMR (400 MHz, _CDCl3 ) _δH 5.35 (d, J=5.2 Hz, 1H), 4.03-3.83 (m, 4H), 3.58-3.47 (m, 1H), 2.34-2.17 (m, 2H), 2.10-1.92 (m, 2H), 1.88-1.61 (m, 6 H), 1.53-1.43 (m, 5H), 1.30 (s, 3H), 1.23-1.06 (m, 3H), 1.01 (s, 3H), 0.96-0.84 (m, 3H), 0.78 (s, 3H).

Synthesis of 18.3 To a solution of 18.2 (10.0 g, 27.7 mmol) in DCM (200 mL) was added Dess-Martin reagent (35.2 g, 83.1 mmol). The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was quenched with saturated NaHCO ₃ (500 mL) and saturated Na ₂ S ₂ O ₃ (200 mL) at 0° C. and stirred for 20 minutes. The mixture was extracted with DCM (2×200 mL). The combined organic layers were washed with saturated NaHCO ₃ (2×200 mL) and saturated brine (200 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give product 18.3 (11.0 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 5.40-5.30 (m, 1H), 4.02-3.87 (m, 4H), 3.28 (d, J = 16.4 Hz, 1H), 2.82 (dd, J = 2.0, 16.4 Hz, 1H), 2.53-2.42 (m, 1H), 2.34-2.26 (m, 1H), 2.13-1.99 (m, 3H), 1.85-1.68 (m, 4H) , 1.55-1.42 (m, 4H), 1.31-1.24 (m, 6H), 1.19 (s, 3H), 1.08-1.00 (m, 2H), 0.81 (s, 3H).

Synthesis of 18.4a and 18.4b. A cold (-70°C) LDA solution (139 mL, 1.0 M, 139 mmol, freshly prepared) was added to a stirred solution of 18.3 (10.0 g, 27.8 mmol) and ethyl diazoacetate (15.8 g, 139 mmol) in THF (160 mL) at -70°C. The mixture was stirred at -70°C for 2 h. Acetic acid (8.34 g, 139 mmol) in THF (40 mL) was then added, and the mixture was then warmed to 20°C and stirred for 16 h. Water (300 mL) and PE (200 mL) were added, the organic phase was separated, and the aqueous phase was extracted with EtOAc (150 mL). The combined organic layers were washed with saturated brine (200 mL), dried over _{anhydrous Na2SO4} , filtered, and concentrated to give the product (13 g), which was used directly in the next step. To a solution of the product (12 g, 25.3 mmol) in DME (100 mL) was added Rh ₂ (OAc) ₄ (335 mg, 0.76 mmol). The reaction mixture was stirred at 25° C. for 16 hours to give a solution. The reaction mixture was concentrated. The residue was purified by silica gel chromatography (0-20% EtOAc in PE) to give a mixture of products 18.4a and 18.4b (6.80 g). ^1H NMR (400 MHz, _CDCl3 ) _δH 12.8-12.6 (m, 0.2H), 5.69-5.44 (m, 1H), 4.29-4.10 (m, 2H), 4.04-3.82 (m, 4H), 3.44-3.17 (m, 0.8H), 2.99-2.65 (m, 1H), 2.48-1.96 (m, 4H), 1.85-1.61 (m, 6H), 1.55-1.40 (m, 3H), 1.34-1.14 (m, 12H), 1.02-0.96 (m, 3H), 0.79 (s, 3H).

Synthesis of 18.5a and 18.5b To a mixture of 18.4a and 18.4b (6.80 g, 15.2 mmol) in MeOH (150 mL) was added H ₂ O (50 mL) and NaOH (6.08 g, 152 mmol). The reaction mixture was stirred at 60° C. for 16 hours to give a mixture. The reaction mixture was concentrated. H ₂ O (150 mL) was then added. The mixture was extracted with EtOAc (3×150 mL). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (0-2% EtOAc in DCM) to give product 18.5a (1.5 g, 26%) and product 18.5b (900 mg, 16%).

18.5a: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 5.57 (d, J = 4.4 Hz, 1H), 4.04-3.82 (m, 4H), 2.67-2.56 (m, 1H), 2.49-2.25 (m, 4H), 2.20-1.97 (m, 3H), 1.84-1.59 (m, 7H), 1.56-1.37 (m, 3H), 1.30 (s, 3H), 1.26-1.03 (m, 4H), 1.00 (s, 3H), 0.79 (s, 3H).

18.5b: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 5.56 (d, J = 4.4 Hz, 1H), 4.05-3.83 (m, 4H), 3.25 (d, J = 14.0 Hz, 1H), 2.82 (d, J = 14.4 Hz, 1H), 2.65-2.53 (m, 1H), 2.24-2.01 (m, 3H), 1.89-1.60 (m, 7H), 1.57-1.39 (m, 4H), 1.30 (s, 3H), 1.28-1.02 (m, 5H), 0.99 (s, 3H), 0.79 (s, 3H).

Synthesis of 18.6 To a solution of BHT (10.6 g, 48.3 mmol) in toluene (100 mL) at 0 °C under nitrogen, trimethylaluminum (2 M in toluene, 12.0 mL, 24.1 mmol) was added dropwise. The mixture was stirred at 25 °C for 1 h and used directly as a solution of MAD without further purification. To the MAD solution, a solution of 18.5a (3.0 g, 8.0 mmol) in anhydrous DCM (20 mL) was added dropwise at −70 °C. After stirring at −70 °C under _{N 2} for 1 h, MeMgBr (8.03 mL, 24.1 mmol, 3 M in ethyl ether) was added dropwise at −70 °C. The resulting solution was stirred at −70 °C for an additional 2 h. The reaction mixture was poured into saturated aqueous citric acid (100 mL) at <10 °C and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure to give the product, which was purified along with another batch (from 300 mg of 18.5a). The residue was triturated with PE (20 mL) at 20 °C to give 18.6 (3.3 g), which was used without further purification or directly in the next step.

Synthesis of 18.7 To a solution of 18.6 (3.30 g, 8.5 mmol) in THF (50 mL) was added 12 M HCl (3 mL, 36.0 mmol). The reaction mixture was stirred at 20° C. for 16 hours to give a solution. The reaction mixture was diluted with H ₂ O (50 mL) and adjusted to pH=9 with solid Na ₂ CO ₃ (20 g). The product was extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the product. The residue was purified by flash column (20-100% EtOAc in PE) to give 18.7 (600 mg) as a solid.

18.7: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 5.40 (d, J = 3.6 Hz, 1H), 2.53 (t, J = 8.8 Hz, 1H), 2.28-2.17 (m, 2H), 2.12 (s, 3H), 2.10-2.01 (m, 2H), 1.92-1.50 (m, 8H), 1.49-1.32 (m, 6H), 1.30-1.19 (m, 7H), 0.91 (s, 3H), 0.63 (s, 3H).

Synthesis of 18.8 To a mixture of MePPh ₃ Br (7.75 g, 21.7 mol) in THF (30 mL) was added t-BuOK (2.43 g, 21.7 mol) under N ₂ at 25° C. The resulting mixture was stirred at 50° C. for 30 min. Compound 18.7 (2.50 g, 7.25 mol) was added in portions while maintaining the temperature below 50° C. The reaction mixture was stirred at 60° C. for 16 h to give a suspension. The reaction mixture was quenched with 10% aqueous NH ₄ Cl (50 mL) at 25° C. The organic layer was separated. The aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic phases were concentrated under reduced pressure to give a solid, which was purified by silica gel chromatography (0-50% EtOAc in PE) to give 18.8 (2.50 g, 99%). ^1H NMR (400 MHz, _CDCl3 ) δ 5.50-5.41 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 2.10-1.94 (m, 3H), 1.93-1.77 (m, 4H), 1.76 (s, 3H), 1.75-1.64 (m, 3H), 1.63-1.56 (m, 2H), 1.55-1.31 (m, 6H), 1.31-1.26 (m, 2H), 1.25 (s, 3H), 1.24-1.05 (m, 5H), 0.89 (s, 3H), 0.59 (s, 1H).

Synthesis of 18.9 To a solution of 18.8 (300 mg, 0.875 mmol) in DCM (5 mL) was added m-CPBA (188 mg, 0.875 mmol). The resulting mixture was stirred at 20° C. for 2 h. The mixture was quenched with saturated aqueous NaHCO ₃ (100 mL) at 20° C. The DCM phase was separated and washed with saturated aqueous NaHCO ₃ /Na ₂ S ₂ O ₃ (1:1, 2×100 mL), brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give 18.9 (350 mg). ^1H NMR (400 MHz, _CDCl3 ) δ 5.46 (s, 1H), 4.85 (s, 1H), 4.70 (s, 2H), 2.89 (d, J = 4.4 Hz, 1H), 2.59-2.48 (m, 1H), 2.59-2.48 (m, 1H), 2.32 (d, J = 4.8 Hz, 1H), 2.26-2.17 (m, 2H), 2.00-1.79 (m, 6H), 1.70-1.64 (m, 4H), 0.98 (s, 8H), 0.89 (s, 2H), 0.81 (s, 1H), 0.69 (s, 3H), 0.58 (s, 5H).

Synthesis of 18 and 19. A solution of 18.9 (350 mg, 0.98 mmol), Cs ₂ CO ₃ (957 mg, 2.92 mmol), and 1H-pyrazole-4-carbonitrile (181 mg, 1.95 mmol) in DMF (10 mL) was stirred at 120° C. for 16 h. The mixture was added to saturated NH ₄ Cl (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with LiCl (50 mL, 3% in water), saturated brine (2×50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (0-20% acetone in DCM) to give 18.10 (70 mg), which was purified by SFC (Column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um); Conditions: 0.1% NH ₃ H ₂ O EtOH; Start B: 45%; End B: 45%; Gradient time (min): n/a; 100% B retention time (min): n/a; Flow rate (ml/min): 70) to give 18 (40.3 mg, 57.6%) and 19 (17.3 mg, 24.7%).

18: ¹ H NMR (400 MHz, _CDCl3 ) δ 7.93 (s, 1H), 7.82 (s, 1H), 5.46 (d, J = 4.0 Hz, 1H), 4.36 (d, J = 13.6 Hz, 1H), 4.09 (d, J = 13.6 Hz, 1H), 2.50 (s, 1H), 2.11-1.94 (m, 3H), 1.93-1.84 (m, 2H), 1.82-1.63 (m, 4H), 1.61-1.55 (m, 2H), 1.54- 1.34 (m, 6H), 1.28-1.25 (m, 2H), 1.25 (s, 3H), 1.23-1.00 (m, 4H), 0.98 (s, 3H), 0.94 (s, 3H), 0.89 (s, 3H). _{LCMS purity ≧99%, MS ESI calculated for C28H38N3 [} M _{-2H2O +} H] ⁺ 416.3, found 416.3.

19: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.83 (s, 1H), 5.48 (d, J = 4.0 Hz, 1H), 4.23-4.16 (m, 1H), 4.07-4.00 (m, 1H), 2.31 (s, 1H), 2.16-1.85 (m, 6H), 1.79-1.67 (m, 3H), 1.65-1.57 (m, 4H), 1.56-1.35 (m, 8H), 1.32-1.28 (m, 2H), 1.27 (s, 3H), 1.26-1.13 (m, 4H), 1.13 (s, 3H), 1.11-1.04 (m, 1H), 0.92 (d, J = 2.4 Hz, 6H). LCMS purity ≧99%, MS ESI calculated for C ₂₈ H ₃₈ N ₃ [M−2H ₂ O+H] ⁺ 416.3, found 416.3.

Examples 20 and 21: 1-((S)-2-hydroxy-2-((1S,3aS,3bR,5aR,7R,10aS,10bR,12aS)-7-hydroxy-7,12a-dimethyloctadecahydrocyclohepta[a]cyclopenta[f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (20) and 1-((R)-2-hydroxy-2-((1S,3aS,3bR,5aR,7R,10aS,10bR,12aS)-7-hydroxy-7,12a-dimethyloctadecahydrocyclohepta[a]cyclopenta[f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (21).
Synthesis of 20.2 To a solution of 20.1 (10 g, 36.4 mmol) in THF (50 mL) was added Pd/C (1 g, dry) and HBr (0.5 mL). The reaction mixture was degassed under reduced pressure and purged with _H2 five times. The mixture was stirred under _H2 at 20 °C for 16 h. The reaction mixture was filtered through a Celite pad and washed with THF (5 x 20 mL). The filtrate was concentrated. The residue was triturated with petroleum ether (10 mL) at 20 °C to give 20.2 (10.31 g). ^1H NMR (400 MHz, _CDCl3 ) _δH 3.75-3.65 (m, 2H), 2.61-2.54 (m, 1H), 2.23-2.04 (m, 6H), 1.87-1.62 (m, 6H), 1.52-1.46 (m, 3H), 1.29-1.07 (m, 7H), 0.77 (s, 3H).

Synthesis of 20.3: To a solution of diisopropylamine (27.9 g, 276 mmol) in anhydrous THF (110 mL) was added n-BuLi (2.5 M in hexane, 110 mL, 276 mmol) dropwise under nitrogen at −70°C. The mixture was stirred at −70°C for 20 minutes. To a solution of 20.2 (20 g, 55.4 mmol) in THF (600 mL) was added ethyl diazoacetate (31.4 g, 276 mmol) under a _N2 atmosphere. Freshly prepared LDA (276 mmol) was then added dropwise at −70°C. The mixture was stirred at −70°C for 4 hours. The reaction was then quenched at −70°C by the addition of acetic acid (22.0 g, 276 mmol) in THF (100 mL). The mixture was then warmed to 25°C and stirred for 12 hours. Water (200 mL) was added. The aqueous solution was extracted with EtOAc (2 x 600 mL). The combined organic layers were washed with brine (1000 mL), dried _{over Na2SO4} , and concentrated to give 20.3 (40.0 g).

Synthesis of 20.4 and 20.4a To a solution of 20.3 (30.0 g) in DME (300 mL) was added _Rh2 (OAc) ₄ (373 mg, 0.84 mmol) at 25°C. The reaction mixture was stirred at 40°C for 12 hours. The reaction mixture was concentrated under reduced pressure to give 20.4 and 20.4a (30.0 g).

Synthesis of 20.5 and 20.5a To a mixture of 20.4 and 20.4a (30.0 g, 82.7 mmol) in MeOH/THF/ _H2O (200 mL/200 mL/50 mL) was added NaOH (33.0 g, 827 mmol). The reaction mixture was stirred at 70°C for 12 hours. The reaction mixture was extracted with ethyl acetate (2 x 500 mL). The combined organic phase was washed with water (500 mL), brine (600 _mL ), dried over _Na2SO4 , filtered, and concentrated to give 20.5 and 20.5a (20.0 g). ^1H NMR (400 MHz, _CDCl3 ) _δH 3.67 (br s, 1H), 3.05 (t, J=12.67 Hz, 1H), 2.37-2.52 (m, 2H), 1.82-2.14 (m, 6H), 1.62-1.78 (m, 6H), 0.94-1.46 (m, 8H), 0.77 (s, 3H).

Synthesis of 20.6 and 20.6a A solution of 20.5 and 20.5a (20.0 g, 68.8 mmol) in DCM (300 mL) was added to DMP (58 g, 137 mmol) under _N2 . The reaction mixture was stirred under _N2 at 15 °C for 2 hours to give a mixture. The mixture was poured into saturated aqueous _NaHCO3 (500 mL), followed by the addition of saturated _{aqueous Na2S2O3} ( ₅₀₀ mL). The aqueous phase was extracted with DCM (3 x 200 mL). The combined organic phase was washed with brine (2 x 500 mL), dried _over anhydrous _Na2SO4 , filtered, concentrated and purified by flash column (0-20% EtOAc in PE) to give 20.6 and 20.6a (14.5 g, 73.2%), which was purified by SFC (Column DAICEL CHIRALPAK IC (250 mm * 50 mm, 10 um) Conditions 0.1% _{NH3H2O ETOOH} Start B 40% End B 40% Gradient time (min) 100% B Purification by flash column (0-30% EtOAc in PE) gave 20.6a (3.8 g) as a solid and 20.6 (9 g) as a solid, which was repurified by flash column (0-30% EtOAc in PE) to give 20.6 (3.5 g, 24.3%). 20.6a was purified by flash column (0-20% EtOAc in PE) to give 20.6a (3.5 g, 13.1 mmol).

20.6: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 3.04 (t, J = 12.55 Hz, 1H), 2.35-2.55 (m, 3H), 1.91-2.17 (m, 5H), 1.50-1.88 (m, 10H), 0.99-1.45 (m, 7H), 0.90 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calculated for C19H29O2[M+H]+ 289.3 found 289.3.

20.6a: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.24-2.63 (m, 5H), 1.88-2.17 (m, 5H), 1.63-1.86 (m, 6H), 1.06-1.60 (m, 10H), 0.90 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₁₉ H ₂₉ O ₂ [M+H] ⁺ 289.3 found 289.3.

Synthesis of 20.7 To a solution of 2,6-di-tert-butyl-4-methylphenol (15.9 g, 72.6 mmol) in toluene (40 mL) was added _AlMe (18.1 mL, 36.3 mmol, 2 M in toluene) dropwise at 0°C. The mixture was stirred at 25°C for 30 minutes. A solution of 20.6 (3.5 g, 12.1 mmol) in anhydrous DCM (5 mL) was added dropwise to a solution of MAD (36.3 mmol) at −70°C. After stirring at −70°C for 1 hour, MeMgBr (12.1 mL, 36.3 mmol, 3 M in ethyl ether) was added dropwise at −70°C and stirred at −70°C for 1 hour. The reaction mixture was poured into saturated aqueous citric acid (50 mL) below 10°C. The aqueous solution was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (80 mL), dried over Na ₂ SO ₄ and evaporated under reduced pressure to give the product. The product was purified by flash column (10-30% EtOAc in PE) to give 20.7 (1.8 g). Compound 20.7 (200 mg) was purified by flash column (0-30% EtOAc in PE) to give 20.7 (14.3 mg).
20.7: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.44 (dd, J = 19.20, 8.16 Hz, 1H), 1.75-2.16 (m, 8H), 1.58-1.66 (m, 2H), 1.41-1.53 (m, 4H), 0.95-1.40 (m, 13H), 0.89 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₀ H ₃₁ O[MH ₂ O+H] ⁺ 287.3 found 287.3.

Synthesis of 20.8 To a solution of t-BuOK (2.19 g, 19.6 mmol) in THF (20 mL) was added EtPPh ₃ Br (7.27 g, 19.6 mmol) under N ₂ at 40° C. The mixture was stirred at 40° C. for 30 minutes to give a solution. Then, compound 20.7 (2.0 g, 6.56 mmol) in THF (10 ml) was added. The mixture was stirred at 40° C. for 30 minutes to give a solution. The mixture was poured into water (30 mL) and stirred for 20 minutes. The aqueous phase was extracted with EtOAc (3×40 mL). The combined organic phase was washed with brine (2×30 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-10% EtOAc in PE) to give 20.8 (1.6.0 g, 77.2%). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 5.05-5.24 (m, 1H), 1.95-2.43 (m, 5H), 1.61-1.94 (m, 8H), 1.15-1.53 (m, 15H), 0.92-1.14 (m, 4H), 0.89 (s, 3H).

Synthesis of 20.9 To a solution of 20.8 (1.6 g, 5.05 mmol) in THF (30 mL) was added 9-BBN dimer (2.44 g, 10.1 mmol) under _N2 . The reaction mixture was stirred at 50°C for 2 h under _N2 and cooled to 0°C. To the reaction mixture were added ethanol (4.40 mL, 75.7 mmol) and NaOH (15.1 _mL , 5 M, 75.7 mmol). Then, _H2O2 (8.56 g, 30%, 75.7 mmol) was added dropwise at 15°C. The mixture was stirred at 50°C for 2 h. Saturated _{aqueous Na2S2O3} ( ₅₀ mL) was added, and the mixture was stirred at 0° _C for an additional 1 h. The reaction was checked with potassium iodide-starch test paper to ensure that excess _H2O2 was destroyed. The aqueous phase was extracted with EtOAc (3 x 40 mL). The combined organic phases were washed with brine (2 x 50 _mL ), dried over anhydrous _Na2SO4 , filtered and concentrated to give 20.9 (1.0 g).

Synthesis of 20.10 To a solution of 20.9 (1.0 g, 2.98 mmol) in DCM (30 mL) was added DMP (1.44 g, 5.96 mmol) under _N2 . The reaction mixture was stirred under _N2 at 15 ° _C for 2 h to give a mixture. The mixture was added to saturated aqueous _NaHCO3 (50 mL) and saturated _Na2S2O3 ( ₅₀ mL) was added. The aqueous phase was extracted with DCM (3 x 40 mL). The combined organic phases were washed with brine (2 x 50 _mL ), dried over anhydrous _Na2SO4 , filtered, concentrated, and purified by flash column (0-20% EtOAc in PE) to give 20.10 (0.8 g, 81%). ^1H NMR (400 MHz, _CDCl3 ) _δH 2.55 (t, J=8.91 Hz, 1H), 2.16 (br d, J=9.29 Hz, 1H), 2.12 (s, 3H), 1.95-2.05 (m, 2H), 1.71-1.92 (m, 4H), 1.37-1.70 (m, 10H), 0.87-1.35 (m, 13H), 0.63 (s, 3H).

Synthesis of 20.11 To a solution of t-BuOK (1.0 g, 9.00 mmol) in THF (20 mL) was added MePPh _Br (3.21 g, 9.00 mmol) at 50° C. under N _2. The mixture was stirred at 50° C. for 30 minutes to give a solution. 20.10 (1.0 g, 3.00 mmol) in THF (10 mL) was added. The mixture was stirred at 50° C. for 30 minutes to give a solution. The mixture was poured into water (30 mL) and stirred for 20 minutes. The aqueous phase was extracted with EtOAc (3×40 mL). The combined organic phase was washed with brine (2×20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-10% EtOAc in PE) to give 20.11 (800 mg, 80.7%). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 4.85 (s, 1H), 4.71 (s, 1H), 1.77-2.05 (m, 6H), 1.62-1.71 (m, 3H), 1.35-1.60 (m, 9H), 1.08-1.33 (m, 12H), 0.83-1.03 (m, 4H), 0.58 (s, 3H).

Synthesis of 20.12 To a solution of 20.11 (150 mg, 0.4537 mmol) in DCM (10 mL) was added m-CPBA (156 mg, 0.9074 mmol, 80%) at 0° C. The solution was stirred at 25° C. for 1 h to give a suspension. The mixture was quenched with saturated NaHCO ₃ and Na ₂ S ₂ O ₃ (40 mL, 1:1) and extracted with DCM (3×20 mL). The combined organic phase was washed with saturated NaHCO ₃ and Na ₂ S ₂ O ₃ (60 mL, 1:1), dried over Na ₂ SO ₄ , filtered, and concentrated to give 20.12 (220 mg).

Synthesis of 20 and 21. A mixture of 20.12 (220 mg, 0.6348 mmol), Cs ₂ CO ₃ (619 mg, 1.90 mmol), and 1H-pyrazole-4-carbonitrile (117 mg, 1.26 mmol) in DMF (10 mL) was stirred at 130° C. for 12 hours to give a suspension. The mixture was poured into saturated NH ₄ Cl (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with LiCl (50 mL, 5% in water), brine (2×50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, and purified by column (0-50% EtOAc in PE) to give 20 and 21 (300 mg). The diastereomers were purified by SFC (column DAICEL CHIRALPAK AD-H (250 mm * 30 mm, 5 um) conditions 0.1% NH ₃ H ₂ O ETOH Start B 40 End B 40 Gradient time (min) 100% B Retention time (min) Flow rate (ml/min) 60) to give 21 (51.2 mg, 16%, Rt=4.210 min) as a solid and 20 (124.2 mg, 39.8%, Rt=4.855 min).

21: ^1H NMR (400 MHz, _CDCl3 ) _δH 7.90 (s, 1H), 7.81 (s, 1H), 4.11-4.25 (m, 1H), 3.93-4.08 (m, 1H), 2.29 (s, 1H), 1.75- 2.11 (m, 6H), 1.64-1.72 (m, 3H), 1.35-1.52 (m, 5H), 0.93-1.31 (m, 13H), 0.89 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₇ H ₃₈ N ₃ [M-2H ₂ O+H] ⁺ 404.3 found 404.3. SFC 100% de.

20: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.94 (s, 1H), 7.82 (s, 1H), 4.36 (d, J = 13.76 Hz, 1H), 4.09 (d, J = 13.76 Hz, 1H), 2.49 (s, 1H), 1.93-2.06 (m, 2H), 1.62-1.90 (m, 7H), 1.36-1.57 (m, 9H), 1.01-1.33 (m, 12H), 0.98 (s, 3H), 0.94 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₇ H ₃₈ N ₃ [M-2H ₂ O+H] ⁺ 404.3 found 404.3. SFC 100% de.

Examples 22 and 23: 1-((S)-2-hydroxy-2-((1S,3aS,3bR,5aS,8S,10aS,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyloctadecahydrocyclohepta[a]cyclopenta[f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (22) and 1-((R)-2-hydroxy-2-((1S,3aS,3bR,5aS,8S,10aS,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyloctadecahydrocyclohepta[a]cyclopenta[f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (23).
Synthesis of 22.2 To a solution of 22.1 (13 g, 41.3 mmol) in THF (400 mL) was added ethyl diazoacetate (23.5 g, 206 mmol) under _N2 , followed by LDA (206 mmol) at −70 °C. After stirring at −70 °C for 4 h, a solution of acetic acid (16.4 g, 206 mmol) in THF (100 mL) was added to quench the reaction at −70 °C. The mixture was then warmed to 25 °C, stirred for 12 h, and treated with water (200 mL). The aqueous solution was extracted with diethyl ether (2 × 300 mL). The combined organic layers were washed with brine (300 mL), dried _{over Na2SO4} , and concentrated to give 22.2 (17 g). ^1H NMR (400 MHz, _CDCl3 ) _δH 4.88-4.79 (m, 1H), 4.75-4.67 (m, 1H), 4.37-4.19 (m, 4H), 3.52-3.28 (m, 1H), 2.0 1-1.82 (m, 3H), 1.75 (s, 11H), 1.47-1.31 (m, 7H), 0.99-0.63 (m, 7H), 0.55 (s, 3H).

Synthesis of 22.3 and 22.3a To a solution of 22.2 (17 g, 41.0 mmol) in DME (50 mL) was added _Rh2 (OAc) ₄ (271 mg, 0.615 mmol) at 25°C. The reaction mixture was stirred at 40°C for ₂ hours. The reaction mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with water (30 mL), brine (30 mL), dried over _Na2SO4 , filtered, and concentrated under reduced pressure to give 22.3 and 22.3a (16 g).

Synthesis of 22.4 and 22.4a To a mixture of 22.3 and 22.3a (16 g, 5.54 mmol) in MeOH/THF/H ₂ O (200 mL/100 mL/50 mL) was added NaOH (15.9 g, 399 mmol). The reaction mixture was stirred at 70° C. for 12 h. The reaction mixture was extracted with ethyl acetate (4×500 mL). The combined organic phase was washed with water (500 mL), brine (200 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the product, which was purified by flash column (0-10% EtOAc in PE) to give 22.4 and 22.4a (13 g). The mixture of 22.4 and 22.4a was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 um); condition: 0.1% NH ₃ H ₂ O ETOH; start B 30% end B 30%; flow rate (ml/min): 200) to give 22.4 (3.3 g) and 22.4a (3.0 g).

22.4: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 4.84 (s, 1H), 4.70 (s, 1H), 2.63-2.39 (m, 3H), 2.35-2.26 (m, 1H), 2.06-1.95 (m, 2H) ), 1.75 (s, 10H), 1.41-1.10 (m, 10H), 0.98-0.86 (m, 1H), 0.81 (s, 4H), 0.56 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₃ H ₃₇ O [M+H] ⁺ 329.3, found 329.3, C ₂₃ H ₃₅ [M−H ₂ O+H] ⁺ 311.3, found 311.3.

22.4a: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 4.84 (s, 1H), 4.70 (s, 1H), 2.81 (dd, J = 11.2, 15.2 Hz, 1H), 2.53-2.30 (m, 2H), 2.12-1.90 (m, 3H), 1.89-1.81 (m, 1H), 1.75 ( s, 10H), 1.49-1.00 (m, 9H), 0.88 (s, 4H), 0.82-0.73 (m, 1H), 0.56 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₃ H ₃₇ O [M+H] ⁺ 329.3, found 329.3, C ₂₃ H ₃₅ [M−H ₂ O+H] ⁺ 311.3, found 311.3.

Synthesis of 22.5: To a solution of 2,6-di-tert-butyl-4-methylphenol (12.8 g, 58.4 mmol) in toluene (40 mL) was added _AlMe (14.6 mL, 29.2 mmol, 2 M in toluene) dropwise at 0°C. The mixture was stirred at 25°C for 30 minutes and used as a MAD solution. To a solution of 22.4 (3.2 g, 9.74 mmol) in anhydrous DCM (20 mL) was added MAD (29.2 mmol) dropwise at −70°C. After stirring at −70°C for 1 hour, MeMgBr (9.73 mL, 29.2 mmol, 3 M in ethyl ether) was added dropwise at −70°C and stirred at −70°C for 1 hour. The reaction mixture was poured into saturated aqueous citric acid (15 mL) below 10°C. The aqueous solution was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ and evaporated under reduced pressure to give the product. The product was purified by flash column (10-30% EtOAc in PE) to give 22.4 (1.1 g, recovered) and 22.5 (2.0 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 4.90-4.78 (m, 1H), 4.74-4.65 (m, 1H), 2.07-1.96 (m, 1H), 1.75 (s, 13H), 1.46-1.24 (m, 5H), 1.20 (s, 11H), 0.82-0.79 (m, 1H), 0.75 (s, 3H), 0.55 (s, 3H).

Synthesis of 22.6 To a solution of 22.5 (300 mg, 0.87 mmol) in DCM (6 mL) was added m-CPBA (352 mg, 85%, 1.74 mmol) at 15° C. After stirring at 15° C. for 1 h to give a solution, the mixture was quenched with saturated aqueous NaHCO ₃ (10 mL) at 15° C. The DCM phase was separated and washed with saturated aqueous NaHCO ₃ /Na ₂ S ₂ O ₃ (1:1, 2×10 mL), brine (10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give 22.6 (300 mg).

Synthesis of 22 and 23. A solution of 22.6 (300 mg, 0.8319 mmol), Cs ₂ CO ₃ (811 mg, 2.49 mmol), and 1H-pyrazole-4-carbonitrile (154 mg, 1.66 mmol) in DMF (10 mL) was stirred at 130° C. for 12 hours to give a solution. The mixture was poured into saturated NH ₄ Cl (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with LiCl (100 mL, 5% in water), brine (2×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, and purified by column chromatography (0-30% EtOAc in PE) to give 22 and 23 (260 mg).

22 and 23 (260 mg) were purified by SFC (Column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); Conditions: 0.1% NH ₃ H ₂ O IPA; Start B 50% End B 50%; Flow rate (ml/min) 70) to give 23 (50.6 mg, 19.5%, Rt = 1.627 min) and 22 (72.4 mg, 27.9%, Rt = 1.247 min).

22: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.92 (s, 1H), 7.81 (s, 1H), 4.35 (d, J = 14.0 Hz, 1H), 4.08 (d, J = 13.6 Hz, 1H), 2.48 (s, 1H), 2.05-1.97 (m, 1H), 1.92-1.81 (m, 1H), 1.80-1.56 (m, 8H), 1.44-1.24 (m, 7H), 1.22-0.87 (m, 17H), 0.76 (s, 4H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₈ H ₄₀ N ₃ O ₂ [M-2H ₂ O+H] ⁺ 418.3, found 418.3. SFC 100% de.

23: ^1H NMR (400 MHz, _CDCl3 ) _δH 7.88 (s, 1H), 7.80 (s, 1H), 4.20-4.11 (m, 1H), 4.04-3.97 (m, 1H), 2.27 (s, 1H), 2.08-1.99 (m, 1H) ), 1.96-1.82 (m, 2H), 1.75-1.56 (m, 7H), 1.20 (s, 16H), 1.09 (s, 4H), 0.86 (s, 4H), 0.76 (s, 4H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₈ H ₄₀ N ₃ O ₂ [M-2H ₂ O+H] ⁺ 418.3, found 418.3. SFC 99% de.

Examples 24 and 25: 1-((R)-2-hydroxy-2-((1S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-4,8,12a-trimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (24) and 1-((S)-2-hydroxy-2-((1S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-4,8,12a-trimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (25)
Synthesis of 24.2 To a solution of t-BuOK (3.86 g, 34.4 mmol) in THF (110 mL) was added 24.1 (5.0 g, 17.2 mmol) at 25°C under _N2 . The mixture was stirred at 25°C for 10 min. Then, methyl benzenesulfinate (5.37 g, 34.4 mmol) was added. The mixture was stirred at 30°C for 0.5 h. The mixture was quenched with _H2O (200 mL) and extracted with EtOAc (200 x 3 mL). The organic layer was separated, dried _{over Na2SO4} , filtered, and concentrated under reduced pressure to give 24.2 (8.7 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.70-7.45 (m, 10H), 3.52-3.42 (m, 1H), 3.25 (t, J=11.6 Hz, 1H), 2.43-2.29 (m, 1H), 1.86-1.75 (m, 7H), 1.64-1.58 (m, 3H), 1.42-1.34 (m, 8H), 0.93 (s, 3H).

Synthesis of 24.3 To a mixture of 24.2 (8.7 g, 20.9 mmol) in xylene (110 mL) was added Na ₂ CO ₃ (33.1 g, 313 mmol) in portions. The reaction mixture was stirred under N ₂ at 130° C. for 12 h. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography (0-15% EtOAc in PE) to give product 24.3 (3.7 g, 61.4%). ^1H NMR (400 MHz, _CDCl3 ) _δH 7.52 (d, J=6.0 Hz, 1H), 6.10-5.93 (m, 1H), 2.41-2.30 (m, 1H), 1.90-1.67 (m, 7H), 1.62-1.48 (m, 4H) , 1.45-1.37 (m, 5H), 1.35-1.30 (m, 2H), 1.28 (s, 3H), 1.26-1.23 (m, 1H), 1.07 (s, 3H).

Synthesis of 24.4 To a solution of MeMgBr (17.0 mL, 51.2 mmol, 3 M) in THF (30 mL) was added CuI (7.31 g, 38.4 mmol) at 0° C. and stirred at 0° C. for 1 h, then 24.3 (3.7 g, 12.8 mmol) in THF (40 mL) was added at 0° C. After stirring at 0° C. for 3 h, the mixture was poured into saturated NH ₄ Cl (200 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0% to 70% EtOAc in PE) to give 24.4 (3.40 g, 87.4%). ^1H NMR (400 MHz, _CDCl3 ) _δH 2.54-2.36 (m, 2H), 2.30-2.18 (m, 1H), 1.93-1.79 (m, 3H), 1.77-1.61 (m , 4H), 1.55-1.46 (m, 3H), 1.44-1.35 (m, 5H), 1.27 (s, 4H), 1.10 (d, J = 7.3 Hz, 3H), 1.03 (s, 3H), 0.93-0.80 (m, 4H).

Synthesis of 24.5 LDA (27.7 mL, 55.5 mmol) (2 M in THF) was added to a stirred solution of 24.4 (3.4 g, 11.1 mmol) and ethyl diazoacetate (7.03 g, 55.5 mmol, 90%) in THF (70 mL) at −70° C. The mixture was stirred at −70° C. for 2 h. Acetic acid (3.17 mL, 55.5 mmol) in THF (30 mL) was then added and the mixture was warmed to 20° C. for 16 h. Water (300 mL) was then added. The aqueous phase was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 24.5 (4.64 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.79 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 4.00-3.85 (m 2H), 2.46 (s, 3H), 1.91-1.59 (m, 7H), 1.50-1.29 (m, 9H), 1.26 (s, 5H), 1.24-0.87 (m, 14H), 0.83 (t, J=6.7 Hz, 3H), 0.52 (s, 3H).

Synthesis of 24.6 To a solution of 24.5 (6.64 g) in DME (100 mL) was added _Rh2 (OAc) ₄ (121 mg, 0.275 mmol) in one portion at 20°C. The mixture was stirred at ₂₀ °C for 16 h. The mixture was treated with _H2O (200 mL). The mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over anhydrous _Na2SO4 , filtered, and concentrated to give 24.6 (4.29 g). ^1H NMR (400 MHz, _CDCl3 ) _δH 4.23-4.19 (m, 2H), 2.30-2.16 (m, 2H), 1.93-1.64 (m, 8H), 1.62-1.51 (m, 3H), 1.48-1.36 (m, 9H), 1.35-1.28 (m, 11H), 1.23 (s, 3H), 1.08 (d, J = 7.3 Hz, 3H), 1.04-0.94 (m, 2H), 0.84 (d, J=7.3 Hz, 2H).

Synthesis of 24.7 To a mixture of 24.6 (4.29 g) in MeOH (50 mL) was added H ₂ O (130 mL) and KOH (3.66 g, 65.3 mmol). The reaction mixture was stirred at 60° C. for 2 hours to give a mixture. The reaction mixture was concentrated. Then, H ₂ O (200 mL) was added. The mixture was extracted with EtOAc (3×150 mL). The combined organic phases were washed with saturated brine (2×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc in PE) to give 24.7 (2.0 g, 57.6%). ^1H NMR (400 MHz, _CDCl3 ) _δH 2.85-2.72 (m, 1H), 2.22-2.10 (m, 2H), 1.90-1.82 (m, 3H), 1.80-1.70 (m, 4H), 1 .68-1.53 (m, 3H), 1.51-1.27 (m, 10H), 1.26 (s, 3H), 1.16 (s, 3H), 1.06 (d, J=7.2) Hz, 3H), 1.03-0.95 (m, 1H).

Synthesis of 24.8 To a mixture of EtPPh ₃ Br (7.68 g, 20.7 mmol) in THF (50 mL) was added t-BuOK (2.32 g, 20.7 mmol) under N ₂ at 20° C. The resulting mixture was stirred at 60° C. for 30 min. 24.7 (1.1 g) in THF (20 mL) was added portionwise below 60° C. The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was quenched with 10% aqueous NH ₄ Cl (20 mL) at 15° C. The organic layer was separated. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (2×20 mL), filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-5% ethyl acetate in PE) to give 24.8 (1 g, 87.7%). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 5.34-5.01 (m, 1H), 2.41 (d, J=14.1 Hz, 1H), 2.34-1.96 (m, 3H), 1.94-1.85 (m, 1H), 1.82-1.69 (m, 4H), 1.67-1.57 (m, 5H) , 1.45-1.30 (m, 8H), 1.26 (s, 6H), 1.23-1.04 (m, 4H), 1.01 (s, 3H), 0.95-0.84 (m, 6H).

Synthesis of 24.9 To _a solution of 24.8 (2.0 g, 6.05 mmol) in THF (30 mL) was added _BH3.Me2S (2.42 mL, 24.2 mmol, 10 M) and stirred at 25 °C for 16 h. To the resulting mixture was added ethanol (6.05 mL, 60.5 mmol, 10 M) at 15 °C, followed by dropwise addition of aqueous NaOH (12.1 mL, 5.0 M, 60.5 mmol) at 0 °C. Hydrogen peroxide (6.05 mL, 10 M, 60.5 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 70 °C for 1 h. The mixture was cooled to 15 ° _C , and _Na2S2O3 (100 mL, saturated aqueous solution) was added. The aqueous solution was extracted with EtOAc (100 _mL × 3). The combined organic layers were washed with brine (2 x 50 mL), dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-50% EtOAc in PE) to give 24.9 (1.8 g, 85.7%). ^1H NMR (400 MHz, _CDCl3 ) _δH 4.17-4.08 (m, 1H), 2.98 (s, 1H), 2.03-1.74 (m, 5H), 1.72-1.32 (m, 14H), 1.31-1.23 (m, 8H), 1.20-1.11 (m, 3H), 1.09-0.92 (m, 5H), 0.90-0.74 (m, 4H).

Synthesis of 24.10 To a solution of 24.9 (1.75 g, 5.02 mmol) in DCM (40 mL) was added Dess-Martin reagent (4.24 g, 10.0 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 20 minutes. The mixture was quenched with saturated aqueous NaHCO ₃ (30 mL) at 10° C. The DCM phase was separated and washed with saturated aqueous NaHCO ₃ /Na ₂ S ₂ O ₃ (1:1, 3 × 50 mL), brine (2 × 20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-60% ethyl acetate in PE) to give 24.10 (1.1 g, 63.5%). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.51-2.44 (m, 1H), 2.26 (dd, J=2.9, 12.7 Hz, 1H), 2.16-2.11 (m, 3H), 2.04-1.73 (m, 6H), 1.70-1.46 (m, 9H), 1.44-1.29 (m, 7H), 1.26-1.22 (m, 3H), 1.20-1.02 (m, 3H), 1.00 (d, J=4.5) Hz, 3H), 0.83 (dd, J=3.1, 7.4 Hz, 3H).

Synthesis of 24.11 To a solution of 24.10 (1.1 g, 3.17 mmol) in MeOH (10 mL) was added MeONa (3.42 g, 63.4 mmol) at 0° C., and the reaction was stirred at 80° C. for 16 hours. The residue was then poured into saturated NH ₄ Cl (100 mL). The aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 24.11 (1.0 g, 91.7%). ^1H NMR (400 MHz, _CDCl3 ) _δH 2.26 (dd, J=3.0, 12.8 Hz, 1H), 2.15 (s, 3H), 2.04-1.97 (m, 1H), 1.90-1.82 (m, 2H), 1.81-1.75 (m, 2H), 1.71-1.57 (m, 4H), 1.50-1.30 (m, 10H), 1.27 (s, 6H), 1.09-1.00 (m, 2H), 0.99 (s, 3H), 0.97-0.92 (m, 1H), 0.83 (d, J = 7.5 Hz, 3H). LC-ELSD/MS purity: 99%, MS ESI calculated for C ₂₃ H ₃₈ O ₂ [M−H ₂ O+H] ⁺ 329.2, found C ₂₃ H ₃₈ O ₂ [M−H ₂ O+H] ⁺ 329.3.

Synthesis of 24.12 To a mixture of MePPh ₃ Br (7.36 g, 20.7 mmol) in THF (80 mL) was added t-BuOK (2.32 g, 20.7 mmol) at 20° C. under N ₂ . The resulting mixture was stirred at 60° C. for 30 min. Compound 24.11 (900 mg, 2.59 mmol) in THF (10 mL) was added in portions below 60° C. The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was quenched with 10% aqueous NH ₄ Cl (200 mL) at 15° C. The organic layer was separated. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine (2×50 mL), filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-20% ethyl acetate in PE) to give 24.12 (770 mg, 86.3%). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 4.80 (s, 1H), 4.62 (d, J=2.0 Hz, 1H), 2.01-1.59 (m, 12H), 1.55-1.46 (m, 3H), 1.43-1.28 (m, 7H), 1.26 (s, 5H), 1.22-1.15 (m, 1H), 1.08-0.92 (m, 4H), 0.90 (s, 3H), 0.82 (d, J=7.5 Hz, 3H).

Synthesis of 24.13 To a mixture of 24.12 (300 mg, 0.8706 mmol) in DCM (5 ml) was added m-CPBA (374 mg, 1.74 mmol, 80% purity). The mixture was stirred at 25° C. for 12 h. Saturated aqueous NaHCO ₃ (30 mL) and Na ₂ S ₃ O ₃ (30 mL) were added and the mixture was stirred for an additional 5 min. The aqueous phase was extracted with DCM (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 24.13 (180 mg). ^1H NMR (400 MHz, _CDCl3 ) _δH 2.73 (d, J=5.0 Hz, 1H), 2.65 (d, J=4.8 Hz, 1H), 2.05-1.82 (m, 3H), 1.80-1.72 (m, 3H), 1.71-1.61 (m, 5H), 1.55-1.46 (m, 4H), 1.42-1.29 (m , 6H), 1.26 (s, 4H), 1.25 (s, 3H), 1.23-1.03 (m, 4H), 1.00 (s, 3H), 0.97-0.88 (m, 3H), 0.80 (d, J = 7.3 Hz, 3H).

Synthesis of 24 and 25 To a solution of 24.13 (180 mg, 0.4991 mmol) in DMF (5 mL) was added 1H-pyrazole-4-carbonitrile (138 mg, 1.49 mmol) and Cs ₂ CO ₃ (488 mg, 1.49 mmol) at 25° C. The mixture was stirred at 145° C. for 48 h. The mixture was washed with water (5 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0% to 70% EtOAc in PE) to give 24 (49.6 mg, 21.9%) and 25 (20 mg). Compound 25 (20 mg) was further purified by SFC (Column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 um); Mobile phase: A: CO ₂ B: 0.1% NH ₃ H ₂ O IPA; Gradient: 50% to 50% B, Flow rate (ml/min): 80) to give 25 (9.4 mg, 4.15%).

24: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.91 (s, 1H), 7.79 (s, 1H), 4.49-4.12 (m, 2H), 2.41 (s, 2H), 2.07-2.00 (m, 1H), 1.91-1.84 (m, 1H), 1.81-1.73 (m, 2H) ), 1.70-1.59 (m, 5H), 1.48-1.31 (m, 7H), 1.27 (s, 7H), 1.11 (s, 3H), 1.07-1.03 (m, 1H), 1.01 (s, 5H), 0.81 (d, J = 7.5 Hz, 3H). LC-ELSD/MS purity: 99%, MS ESI calculated for C ₂₈ H ₄₃ N ₃ O ₂ [M-2H ₂ O+H] ⁺ 418.3, observed value C ₂₈ H ₄₃ N ₃ O ₂ [M-2H ₂ O+H] ⁺ 418.4.

25: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.87 (d, J = 1.8 Hz, 2H), 4.30 (d, J = 13.9 Hz, 1H), 4.01 (d, J = 13.9 Hz, 1H), 3.11 (s, 1H), 2.44 (d, J=5.6 Hz, 1H), 2.10-1.92 (m, 1H), 1.91-1.80 (m, 1H), 1.79-1.70 (m, 2H), 1.68-1.57 (m, 3H), 1.52-1.28 (m , 9H), 1.25 (s, 6H), 1.20 (s, 3H), 1.17-1.12 (m, 1H), 1.10 (s, 3H), 1.02-0.83 (m, 5H), 0.79 (d, J = 7.5 Hz, 3H), 0.70 (d, J=11.6 Hz, 1H). LC-ELSD/MS purity: 99%, MS ESI calculated for C ₂₈ H ₄₃ N ₃ O ₂ [M-2H ₂ O+H] ⁺ 418.3, observed value C ₂₈ H ₄₃ N ₃ O ₂ [M-2H ₂ O+H] ⁺ 418.3.

Examples 26 and 27: 1-((S)-2-hydroxy-2-((1S,3S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-3,4,8,12a-tetramethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (26) and 1-((R)-2-hydroxy-2-((1S,3S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-3,4,8,12a-tetramethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (27)
Synthesis of 26.1 To a solution of t-BuOK (4.64 g, 41.4 mmol) in THF (80 mL) was added 24.7 (6.6 g, 20.7 mmol) at 25°C under _N2 . The mixture was stirred at 25°C for 10 min. Then, methyl benzenesulfinate (6.46 g, 41.4 mmol) was added. The mixture was stirred at 30°C for 0.5 h. The mixture was quenched with _H2O (100 mL) and extracted with EtOAc (3 x 80 mL). The organic layer was separated, dried _{over Na2SO4} , filtered, and concentrated under reduced pressure to give 26.1 (9.16 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.81-7.60 (m, 2H), 7.57-7.41 (m, 3H), 4.28 (dd, J = 13.9, 5.4 Hz, 1H), 3.85 (dd, J = 13.8, 5.8 Hz, 1H), 3.79-3.69 (m, 1H), 3.60-3.42 (m, 1H), 2.45-2.13 (m, 1H), 1.96-1.58 ( m, 6H), 1.54-1.30 (m, 6H), 1.28-1.23 (m, 5H), 1.08 (s, 1H), 1.05-0.90 (m, 3H).

Synthesis of 26.2 To a mixture of 26.1 (9.16 g, 20.6 mmol) in xylene (100 mL) was added Na ₂ CO ₃ (32.7 g, 309 mmol) in portions. The reaction mixture was stirred under N ₂ at 140° C. for 12 h. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc in PE) to give 26.2 (5.2 g, 79.8%). ^1H NMR (400 MHz, _CDCl3 ) _δH 6.86 (dd, J=5.3, 10.0 Hz, 1H), 5.99-5.79 (m, 1H), 2.76-2.49 (m, 1H), 2.02-1.57 (m, 8H), 1.45-1.30 (m, 8H), 1.28 (s, 4H), 1.13-1.09 (m, 6H), 1.05-0.80 (m, 3H).

Synthesis of 26.3 To a solution of MeMgBr (8.39 mL, 25.2 mmol, 3 M) in THF (20 mL) was added CuI (3.59 g, 18.9 mmol) at 0° C. and stirred at 0° C. for 1 h, then 26.2 (2.0 g, 6.31 mmol) in THF (20 mL) was added at 0° C. After stirring at 0° C. for 3 h, the mixture was poured into saturated NH ₄ Cl (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0% to 30% EtOAc in PE) to give 26.3 (1.92 g, 91.8%). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.76 (dd, J=5.0, 14.3 Hz, 1H), 2.11-2.04 (m, 1H), 2.00-1.85 (m, 3H), 1.84-1.56 (m, 9H), 1.44-1.30 (m, 9H), 1.27 (s, 4H), 1.17-1.09 (m, 5H), 1.06 (d, J=7.3 Hz, 3H), 0.99 (d, J=7.0 Hz, 3H).

Synthesis of 26.4 To a mixture of EtPPh ₃ Br (16.0 g, 43.2 mmol) in THF (70 mL) was added t-BuOK (4.84 g, 43.2 mmol) under N ₂ at 20° C. The resulting mixture was stirred at 50° C. for 30 min. Compound 26.3 (1.8 g, 5.17 mmol) in THF (20 mL) was added in portions below 50° C. The reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was quenched with 10% aqueous NH ₄ Cl (200 mL) at 15° C. The organic layer was separated. The aqueous layer was extracted with EtOAc (3×150 mL). The combined organic phases were washed with brine (2×100 mL), filtered, and concentrated under reduced pressure. The residue was purified by flash column (0% to 20% EtOAc in PE) to give 26.4 (1.5 g, 80.6%). ^1H NMR (400 MHz, _CDCl3 ) _δH 5.39-5.16 (m, 1H), 2.42-2.26 (m, 1H), 2.24-2.15 (m, 1H), 1.96-1.87 (m, 1H), 1.82-1.57 (m, 10H), 1.56 (s, 5H), 1.5 4-1.47 (m, 2H), 1.43-1.29 (m, 7H), 1.27 (s, 5H), 1.25-1.17 (m, 3H), 1.06-1.02 (m, 1H), 1.00 (s, 3H), 0.94 (d, J = 7.3 Hz, 3H), 0.88 (d, J=7.0 Hz, 3H).

Synthesis of 26.5 _: A solution of 26.4 (500 mg, 4.35 mmol) in THF (30 mL) was added to _BH3.Me2S (1.73 mL, 17.4 mmol, 10 M) and stirred at 25 °C for 16 h. To the resulting mixture, ethanol (4.34 mL, 43.4 mmol, 10 M) was added at 15 °C, followed by the dropwise addition of aqueous NaOH (8.68 mL, 5.0 M, 43.4 mmol) at 0 °C. Hydrogen peroxide (4.34 mL, 10 M, 43.4 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 80 °C for 1 h. The mixture was cooled to 15 °C, _{and Na2S2O3 (} 150 _mL , saturated aqueous solution) was added. The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (2 x 50 mL), dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-30% EtOAc in PE) to give 26.5 (1.3 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 3.98 (t, J = 6.0 Hz, 1H), 1.91-1.78 (m, 3H), 1.71-1.55 (m, 8H), 1.51-1.36 (m, 13H), 1.27 (d, J = 3.3 Hz, 11H), 1.20 (d, J = 6.3 Hz, 5H), 1.11 (s, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 7.3 Hz, 5H), 0.87-0.78 (m, 5H).

Synthesis of 26.6 To a solution of 26.5 (1 g, 2.75 mmol) in DCM (10 mL) was added Dess-Martin reagent (2.33 g, 5.50 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 20 minutes. The mixture was quenched with saturated aqueous NaHCO ₃ (50 mL) at 10° C. The DCM phase was separated and washed with saturated aqueous NaHCO ₃ /Na ₂ S ₂ O ₃ (1:1, 3 × 50 mL), brine (2 × 20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-30% ethyl acetate in PE) to give 26.6 (740 mg, 74.6%). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 2.54 (dd, J=6.3, 10.0 Hz, 1H), 2.14 (s, 3H), 1.88-1.77 (m, 3H), 1.68-1.52 (m, 10H), 1.49-1.26 (m, 12H) , 1.25 (s, 3H), 1.24-1.18 (m, 2H), 1.14 (s, 3H), 1.09-0.99 (m, 3H), 0.96 (d, J = 6.8 Hz, 4H), 0.91-0.87 (m, 3H).

Synthesis of 26.7 To a solution of 26.6 (640 mg, 1.77 mmol) in MeOH (20 mL) at 0° C. was added MeONa (1.91 g, 35.4 mmol). After stirring at 80° C. for 16 h, the mixture was poured into saturated NH ₄ Cl (100 mL). The aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (0-25% ethyl acetate in PE) to give 26.7 (300 mg, 47.0%). ^1H NMR (400 MHz, _CDCl3 ) _δH 2.52 (d, J=10.5 Hz, 1H), 2.14 (s, 3H), 2.12-2.04 (m, 1H), 1.95-1.73 (m, 5H), 1.69-1.59 ( m, 3H), 1.53-1.31 (m, 9H), 1.27 (s, 5H), 1.23-1.14 (m, 3H), 1.03 (d, J = 7.3 Hz, 3H), 0.97 (s, 4H), 0.86 (d, J=7.5 Hz, 3H).

Synthesis of 26.8 To a mixture of MePPh ₃ Br (2.36 g, 6.65 mmol) in THF (20 mL) was added t-BuOK (746 mg, 6.65 mmol) under N ₂ at 20° C. The resulting mixture was stirred at 80° C. for 30 min. Compound 26.7 (300 mg, 0.8319 mmol) in THF (5 mL) was added in portions below 80° C. The reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was quenched with 10% aqueous NH ₄ Cl (50 mL) at 15° C. The organic layer was separated. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine (2×30 mL), filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-20% EA in PE) to give 26.8 (130 mg, 43.6%). ^1H NMR (400 MHz, _CDCl3 ) _δH 4.81 (s, 1H), 4.64 (s, 1H), 2.09-1.99 (m, 2H), 1.93-1.75 (m, 4H), 1.72 (s, 3H), 1.68-1.59 (m , 3H), 1.55-1.31 (m, 9H), 1.26 (s, 6H), 1.22-1.16 (m, 2H), 1.13-1.06 (m, 2H), 1.04 (d, J = 7.3 Hz, 3H), 0.88 (s, 3H), 0.85 (d, J=7.5 Hz, 3H).

Synthesis of 26.9 To a mixture of 26.8 (130 mg, 0.36 mmol) in DCM (5 ml) was added m-CPBA (156 mg, 0.725 mmol, 80% purity). The mixture was stirred at 25° C. for 12 h. Saturated aqueous NaHCO ₃ (30 mL) and Na ₂ S ₃ O ₃ (30 mL) were added and the mixture was stirred for an additional 5 min. The aqueous phase was extracted with DCM (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 26.9 (150 mg). ^1H NMR (400 MHz, _CDCl3 ) _δH 2.75 (d, J=4.8 Hz, 1H), 2.65 (d, J=4.8 Hz, 1H), 2.04-1.94 (m, 1H), 1.92-1.77 (m, 4H), 1.70-1.58 (m, 4H), 1.56-1.31 (m, 8H), 1.27 ( s, 4H), 1.24 (s, 3H), 1.21-1.07 (m, 4H), 1.03-1.00 (m, 2H), 0.99-0.94 (m, 6H), 0.84 (d, J = 7.5 Hz, 3H).

Synthesis of 26 and 27 To a solution of 26.9 (150 mg, 0.4004 mmol) in DMF (5 mL) was added 1H-pyrazole-4-carbonitrile (111 mg, 1.20 mmol) and Cs ₂ CO ₃ (390 mg, 1.20 mmol) at 25° C. The mixture was stirred at 145° C. for 16 h. The mixture was washed with water (5 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column (0% to 70% EtOAc in PE) to give a mixture of 26 and 27 (180 mg). Purification by SFC (Column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 um); Mobile phase: A: CO ₂ B: 0.1% NH ₃ H ₂ O ETOH; Gradient: 20% to 20% B, Flow rate (ml/min): 70) gave 26 (5.1 mg, 2.72%) and 27 (29.7 mg, 15.8%).

26: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.87 (s, 2H), 4.32-3.94 (m, 2H), 3.36 (s, 1H), 2.46 (d, J = 8.3 Hz, 1H), 1.95-1.57 (m, 8H), 1.52-1.27 (m, 10H), 1.25 (s, 4H), 1.20 (s, 3H) , 1.09 (s, 3H), 1.08-0.98 (m, 3H), 0.96-0.87 (m, 3H), 0.83 (dd, J=5.1, 7.2 Hz, 5H). LC-ELSD/MS purity: 99%, MS ESI calculated for C ₂₉ H ₄₅ N ₃ O ₂ [M-2H ₂ O+H] ⁺ 432.3, observed value C ₂₉ H ₄₅ N ₃ O ₂ [M-2H ₂ O+H] ⁺ 432.4.

27: ^1H NMR (400 MHz, _CDCl3 ) _δH 7.91 (s, 1H), 7.79 (s, 1H), 4.44-4.16 (m, 2H), 2.44-2.36 (m, 2H), 1.93-1.57 (m, 10H) ), 1.54-1.29 (m, 10H), 1.27 (s, 4H), 1.24-1.18 (m, 2H), 1.10 (s, 3H), 1.03 (d, J = 7.3 Hz, 3H), 0.99 (s, 4H), 0.84 (d, J=7.5 Hz, 3H). LC-ELSD/MS purity: 99%, MS ESI calculated for C ₂₉ H ₄₅ N ₃ O ₂ [M-2H ₂ O+H] ⁺ 432.3, observed value C ₂₉ H ₄₅ N ₃ O ₂ [M-2H ₂ O+H] ⁺ 432.3.

Example 30: 1-((R)-2-hydroxy-2-((1S,3aS,3bR,5aS,7S,8aS,8bS,10aS)-7-hydroxy-8a,10a-dimethyl-7-propylhexadecahydrodicyclopenta[a,f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (30)
Synthesis of 30.1 To a solution of pregnanolone (50 g, 157 mmol) in EtOH (250 mL) and THF (250 mL) was added Pd/C (5 g, less than 1% water). The solution was then hydrogenated under 30 psi of hydrogen at 25° C. for 16 hours. The reaction was then loaded with three additional batches of 50 g of pregnanolone. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give 30.1 (188 g, 94%). ^1H NMR (400 MHz, _CDCl3 ) _δH 3.70-3.50 (m, 1H), 2.60-2.45 (m, 1H), 2.25-1.90 (m, 5H), 1.80-1.50 (m, 8H), 1.45-1.05 (m, 10H), 1.00-0.50 (m, 9H).

Synthesis of 30.2: Liquid bromine (45.0 g, 282 mmol) was slowly added to a stirred aqueous NaOH solution (376 mL, 3 M, 1129 mmol) at 0°C. When all the bromine was dissolved, the mixture was diluted with cold dioxane (90 mL) and slowly added to a stirred solution of 30.1 (30 g, 94.1 mmol) in dioxane ( _{210 mL) and water (90 mL). After stirring at 25°C for 5 hours, the remaining oxidizing reagent was quenched with Na2S2O3 ( 300} mL, aqueous), and the mixture was then heated to 80°C until the solid material dissolved. The solution was acidified with HCl (3 M, 50 mL), causing the solid to precipitate. The solid was filtered and washed with water (3 x 100 mL) to give a solid that was dried under reduced pressure to give 30.2 (28 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 3.66-3.51 (m, 1H), 2.37 (t, J=9.2 Hz, 1H), 2.13-2.00 (m, 2H), 1.88-1.77 (m, 3H), 1.75-1.64 (m, 4H), 1.60-1.57 (m, 1H), 1.47-1.32 ( m, 3H), 1.32-1.20 (m, 6H), 1.16-1.04 (m, 2H), 1.04-0.84 (m, 2H), 0.81 (s, 3H), 0.73-0.65 (m, 4H).

Synthesis of 30.3: A mixture of 30.2 (28 g, 87.3 mmol), N,O-dimethylhydroxylamine hydrochloride (16.9 g, 174 mmol), HATU (39.5 g, 104 mmol), and Et ₃ N (50.4 mL, 349 mmol) in anhydrous DCM (350 mL) was stirred at 25° C. for 18 hours. The mixture was then treated with water (200 mL) and extracted with DCM (2×400 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc=5/1) to give 30.3 (24 g, 76%). ^1H NMR (400 MHz, _CDCl3 ) _δH 3.65-3.52 (m, 4H), 3.18 (s, 3H), 2.23-2.09 (m, 1H), 1.84-1.62 (m, 7H), 1.60-1.50 (m, 2H), 1.42-1.3 4 (m, 2H), 1.33-1.22 (m, 6H), 1.19-1.03 (m, 2H), 1.00-0.84 (m, 3H), 0.79 (s, 3H), 0.73-0.65 (m, 4H).

Synthesis of 30.4 Concentrated _H2SO4 (35.1 _mL ) was diluted with _H2O (140 mL). _CrO3 (31.5 g, 316 mmol) was added. The freshly prepared reagent was added to a solution of 30.3 (24 g, 66.0 mmol) in AcOH (300 mL). After stirring at 70 °C for 3 h to give a green solution, the mixture was diluted with water (300 mL) and extracted with DCM (3 x 300 mL). The combined organic phase was washed with brine (2 x 200 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated to give 30.4 (30 g), which was used directly in the next step without further purification.

Synthesis of 30.5 To a solution of 30.4 (30 g) in Ac ₂ O (250 mL) was added NaOAc (23.9 g, 292 mmol). After stirring at 130° C. for 16 hours to obtain a solution, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3×200 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column (10%-20% EtOAc in PE) to give 30.5 (8 g).

Synthesis of 30.6 To a solution of 30.5 (8 g, 23.0 mmol) in MeOH (100 mL) was added NaBH ₄ (2.61 g, 69.0 mmol) at 25° C. After stirring at 25° C. for 30 minutes, the reaction was quenched with water (100 mL) and extracted with DCM (2×100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column (15%-20% EtOAc in PE) to give 30.6 (5.9 g). ^1H NMR (400 MHz, _CDCl3 ) _δH 4.47-4.31 (m, 1H), 3.63 (s, 3H), 3.19 (s, 3H), 2.80-2.76 (m, 1H), 2.24-2.06 (m, 2H), 1.85-1.64 (m, 5H), 1.60-1.43 (m, 7H), 1.32-1.23 (m, 3H), 1.21-1.04 (m, 2H), 1.02-0.93 (m, 2H), 0.90 (s, 3H), 0.74 (s, 3H).

Synthesis of 30.7 To a solution of 30.6 (5.9 g, 16.8 mmol) in THF (100 mL) was added MeMgBr (16.7 mL, 50.4 mmol, 3 M) at −78° C. under N ₂ . The reaction was warmed to 25° C. and stirred at 25° C. for 1 h. The reaction was then quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column (10% to 15% EtOAc in PE) to give 30.7 (4.2 g, 82%). ^1H NMR (400 MHz, _CDCl3 ) _δH 4.46-4.35 (m, 1H), 2.53 (t, J=9.0Hz, 1H), 2.26-2.02 (m, 5H), 2.03-1.94 (m, 1H), 1.75-1.58 (m, 3H), 1.55-1.47 (m, 3H), 1 .46-1.37 (m, 5H), 1.36-1.27 (m, 1H), 1.27-1.09 (m, 4H), 0.91 (s, 3H), 0.88-0.79 (m, 1H), 0.79-0.70 (m, 1H), 0.61 (s, 3H).

Synthesis of 30.8 To a solution of trimethylsulfonium iodide (141 mg, 1.84 mmol) in DMSO (2 mL) was added NaH (73.5 mg, 1.84 mmol, 60% in oil) in THF (1 mL) and stirred at 0°C for 1.0 h under _N2 . Then, a solution of 30.7 (222.9 mg, 0.73 mmol) in DMSO (2 mL) was added at 0°C. After stirring at 25°C for 16 h, the reaction was treated with water (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic phase was washed with water (2 x 5 mL), brine (10 _mL ), dried over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure to give 30.8 (900 mg). ^1H NMR (400 MHz, _CDCl3 ) _δH 4.40-4.39 (m, 1H), 3.68-3.49 (m, 1H), 3.25 (s, 1H), 2.61 (s, 1H), 2.49 (s, 1H), 2.33 (s , 1H), 2.04 (s, 3H), 1.75-1.65 (m, 4H), 1.52-1.45 (m, 4H), 1.37 (s, 10H), 0.79 (s, 7H).

Synthesis of 30.9. To a solution of 30.8 (900 _mg , 2.82 mmol) in DMF (10 mL) was added 4-cyanopyrazole (1.04 g, 11.2 mmol) and _Cs2CO3 (2.75 g, 8.46 mmol). After stirring at 120 °C under _N2 for 16 h, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated to give 30.9 (200 mg), which was purified by SFC (Column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 um); Conditions: 0.1% NH3H2O in ETOH; Start B: 35%; End B: 35%) to give (100 mg, 50.2%). The solid was triturated from MeCN (2 mL) at 25° C. to give 30.9 (84 mg, 84.0%). ^1H NMR (400 MHz, _CDCl3 ) _δH 7.88 (s, 1H), 7.80 (s, 1H), 4.45-4.35 (m, 1H), 4.18-4.12 (m, 1H), 4.04-3.98 (m, 1H), 2.26 (s, 1H), 2.0 4 (s, 4H), 1.75-1.65 (m, 3H), 1.45-1.31 (m, 6H), 1.26-1.14 (m, 4H), 1.11-0.97 (m, 5H), 0.89 (d, J = 13.6 Hz, 8H), 0.74-0.66 (m, 1H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₅ H ₃₄ N ₃ [M-2H ₂ O+H] ⁺ 376.3, found 376.3, analytical SFC 100% de.

Synthesis of 30.10 To a solution of 30.9 (34 mg, 0.083 mmol) in DCM (1 mL) was added Dess-Martin reagent (70 mg, 0.16 mmol) at 20° C. After stirring for 15 min at 20° C., the mixture was poured into saturated aqueous NaHCO ₃ /Na ₂ S ₂ O ₃ (1:1, 20 mL). The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the product, which was purified by preparative HPLC (Column: Phenomenex Gemini-NX 80 mm*40 mm*3 um, Conditions: water (0.05% NH ₃ H ₂ O+10 mM NH ₄ HCO ₃ )-ACN, Start B: 51, End B: 81, Gradient time: 8 min, 100% B Retention time (min): 2.3 min, Flow rate: 30 mL/min) to give 30.10 (5.8 mg, 38.9%). ^1H NMR (400 MHz, _CDCl3 ) _δH 7.88 (s, 1H), 7.80 (s, 1H), 4.21-4.11 (m, 1H), 4.05-3.96 (m, 1H), 2.35 (s, 1H), 2.22-1.82 (m, 7H), 1.81-1.6 2 (m, 5H), 1.52-1.40 (m, 4H), 1.35-1.15 (m, 3H), 1.09 (s, 3H), 1.05-0.95 (m, 2H), 0.89 (s, 3H), 0.84 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₅ H ₃₄ N ₃ O[M−H ₂ O+H] ⁺ 392.4 found 392.4.

Synthesis of 30 To a solution of n-PrMgCl (0.73 ml, 1.46 mmol, 2 M in ether) in THF (1 mL) was added dropwise a solution of 30.10 (100 mg, 0.24 mmol) in THF (1 mL) under _N at −40° C. After stirring at −40° C. for 2 h, the mixture was poured into NH ₄ Cl (1 mL) and extracted with EtOAc (2×5 mL). The combined organic layers were washed with brine (5 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated to give 30 (68 mg), which was purified by SFC (Column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 um); Conditions: 0.1% _{NH3H2O ETOH} ; Start B: 25%; End B: 25%) to give (6.6 mg, 9.72%).

^1H NMR (400 MHz, _CDCl3 ) _δH 7.89 (s, 1H), 7.80 (s, 1H), 4.21-4.10 (m, 1H), 4.06-3.96 (m, 1H), 2.28 (s, 1H), 2.10-1.97 (m, 1H), 1.95-1.80 (m, 1H), 1.78-1.75 ( m, 1H), 1.72-1.59 (m, 5H), 1.54-1.36 (m, 9H), 1.35-1.13 (m, 8H), 1.09 (s, 3H), 0.95-0.91 (m, 6H), 0.87 (s, 3H), 0.75-0.65 (m, 1H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₈ H ₄₀ N ₃ [M-2H ₂ O+H] ⁺ 418.4, found 418.4, analytical SFC 100% de.

Examples 31 and 32: 1-((S)-2-hydroxy-2-((1S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8-(methoxymethyl)-4,12a-dimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (31) and 1-((R)-2-hydroxy-2-((1S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8-(methoxymethyl)-4,12a-dimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (32).
Synthesis of 31.2. A stirred solution of iodotrimethyl-4-sulfane (27.1 g, 133.0 mmol) and NaH (5.31 g, 133.0 mmol, 60%) in DMSO (300 mL) was cooled to 0° C. under N for ₁ h. The mixture was added to a solution of 31.1 (35 g, 127.0 mmol) in DMSO (100 mL) at ₂₅ ° C. for 16 h. The reaction was treated with water (300 mL) and extracted with EtOAc (2×200 mL). The combined organic phase was washed with water (2×200 mL), brine (200 mL), dried over anhydrous _Na SO , filtered, and concentrated under reduced pressure to give 31.2 (40 g).

Synthesis of 31.3 To freshly prepared MeONa (693.0 mmol) in MeOH (400 mL) was added 31.2 (20 g, 69.3 mmol), and the resulting mixture was stirred at 70° C. for 16 h. The reaction was treated with water (200 mL). The aqueous phase was extracted with EtOAc (2×200 mL). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-30% EtOAc in PE) to give 31.3 (10 g, 47.8%). H NMR (400 MHz, CDCl ₃ ) δ _H 3.41-3.36 (m, 5H), 2.61 (s, 1H), 1.97-1.73 (m, 5H), 1.68-1.33 (m, 10H), 1.32-0.99 (m, 8H), 0.91-0.81 (m, 3H).

Synthesis of 31.4 To a solution of t-BuOK (13.2 g, 118 mmol) in THF (400 mL) was added 31.3 (19 g, 59.2 mmol) at 15°C under _N2 . The mixture was stirred at 15°C for 10 min. Then, methyl benzenesulfinate (14.9 mL, 118 mmol) was added. The mixture was stirred at 30°C for 0.5 h. The mixture was quenched with _H2O (500 mL) and extracted with EtOAc (2 x 300 mL). The organic layer was separated, dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure to give 31.4 (27 g).

Synthesis of 31.5: To a mixture of 31.4 (27 g, 60.7 mmol) in xylene (300 mL) was added Na ₂ CO ₃ (98.2 g, 910 mol) in portions. After stirring at 125° C. under _{N 2} for 12 h, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc in PE) to give 31.6 (6.2 g, 32.1%). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.52 (br d, J = 5.8 Hz, 1H), 6.02 (dd, J = 3.1, 5.9 Hz, 1H), 3.47-3.29 (m, 5H), 2.61 (br s, 1H), 2.37 (br d, J=10.0 Hz, 1H), 1.91-1.58 (m, 11H), 1.53-1.29 (m, 7H), 1.07 (s, 3H).

Synthesis of 31.6 To a solution of MeMgBr (19.4 mL, 58.2 mmol, 3 M) in THF (40 mL) was added CuI (11.0 g, 58.2 mmol) at 0° C. After stirring at 0° C. for 1 h, 31.5 (6.2 g, 19.4 mmol) in THF (40 mL) was added at 0° C. After stirring at 0° C. for 3 h, the mixture was poured into saturated NH ₄ Cl (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, and purified by flash column (0% to 40% EtOAc in PE) to give 31.6 (4.5 g, 69.4%). ^1H NMR (400 MHz, _CDCl3 ) _δH 3.46-3.34 (m, 5H), 2.53-2.19 (m, 3H), 1.88-1.56 (m, 10H), 1.53-1.29 (m, 8H), 1.24-1.17 (m, 2H), 1.10 (d, J = 7.3Hz, 3H), 1.03 (s, 3H).

Synthesis of 31.7 To a solution of 31.6 (4.5 g, 13.4 mmol) and ethyl diazoacetate (6.11 g, 53.6 mmol) in THF (150 mL) was added freshly prepared LDA (53.6 mL, 1.0 M, 53.6 mmol) at −78° C. After stirring at −78° C. for 3 hours, acetic acid (3.21 g, 53.6 mmol) in THF (50 mL) was added. The resulting reaction mixture was then stirred at 15° C. for 16 hours. The mixture was poured into water (150 mL). The aqueous phase was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated under reduced pressure to give 31.7 (9.0 g).

Synthesis of 31.8 To a solution of 31.7 (9.0 g) in DME (100 mL) was added Rh ₂ (OAc) ₄ (220 mg, 0.5 mmol) in one portion at 15° C. After stirring at 15° C. for 12 h, the mixture was concentrated to give 31.8 (9 g).

Synthesis of 31.9 To a solution of 31.8 (9 g) in MeOH (100 mL) was added KOH (11.9 g, 213 mmol) at 15° C. After stirring at 70° C. for 1 h, the reaction mixture was poured into H ₂ O (50 mL) and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by flash column (0-15% EtOAc in PE) to give 31.9 (2.3 g, 30.9%). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 3.47-3.30 (m, 5H), 2.79 (ddd, J=7.7, 12.1, 14.4 Hz, 1H), 2.22-2.10 (m, 2H), 1.93-1.47 (m, 13H), 1.46-1.28 (m, 7H), 1.16 (s, 3H), 1.06 (d, J = 7.5 Hz, 3H), 0.99-0.74 (m, 2H).

Synthesis of 31.10. To a suspension of _Ph3PEtBr (12.2 g, 32.9 mmol) in anhydrous THF (80 mL) was added t-BuOK (3.69 g, 32.9 mmol) under _N2 at 15 °C, and the suspension was stirred at 60 °C for 30 min. Then, a solution of 31.9 (2.3 g, 6.59 mmol) in anhydrous THF (50 mL) was added dropwise. After stirring at 60 °C for 16 h, the mixture was cooled, poured into ice-water (100 mL), and stirred for 10 min. The aqueous phase was extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with brine (2 × 200 mL), filtered, concentrated, and purified by flash column (0-10% EtOAc in PE) to give 31.10 (1.9 g, 80.1%). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 5.26-5.03 (m, 1H), 3.45-3.30 (m, 5H), 2.55 (br s, 1H), 2.40 (td, J = 3.4, 14.0 Hz, 1H), 2.29-2.18 (m, 1H), 2.15-2.01 (m, 2H), 1.89 (br d, J=13.8 Hz, 1H), 1.80-1.58 (m, 9H), 1.50-1.13 (m, 11H), 1.09-1.03 (m, 1H), 1.00 (s, 3H), 0.90 (dd, J = 7.4, 15.7 Hz, 4H).

Synthesis of 31.11 To _a solution of 31.10 (1.8 g, 4.99 mmol) in THF (50 mL) was added _BH3.Me2S (14.9 mL, 14.9 mmol, 1 M in THF) at 25°C. After stirring at 50°C for ₁₆ hours, the reaction mixture was cooled and quenched with EtOH (3.18 mL, 2.29 g, 49.9 mmol) at 0°C, followed by the very slow addition of NaOH (9.97 mL, 5 M, 49.9 mmol). After the addition, _H2O2 (4.98 mL, 49.9 mmol, 10 M in water) was added slowly until the internal temperature no longer rose, maintaining the internal temperature below 30°C. The mixture was stirred at 50°C for an additional hour. The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated Na ₂ S ₂ O ₃ (2×100 mL), brine (2×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 31.11 (1.8 g).

Synthesis of 31.12 To a solution of 31.11 (1.8 g, 4.93 mmol) in DCM (50 mL) was added Dess-Martin reagent (4.18 g, 9.86 mmol). After stirring at 25° C. for 30 minutes, the mixture was quenched with saturated aqueous NaHCO ₃ (30 mL). The DCM phase was separated and washed with saturated aqueous NaHCO ₃ /Na ₂ S ₂ O ₃ (1:1, 2×30 mL), brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 31.12 (1.8 g).

Synthesis of 31.12a To a solution of 31.12 (1.9 g, 5.04 mmol) in MeOH (100 mL) was added MeONa (4.08 g, 75.6 mmol) at 0° C. After stirring at 70° C. for 16 hours, the residue was poured into saturated NH ₄ Cl (100 mL). The aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 31.12a (2.1 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 3.45-3.34 (m, 5H), 2.60 (br s, 1H), 2.28 (dd, J=2.9, 12.6 Hz, 1H), 2.16 (s, 3H), 2.05-1.61 (m, 9H), 1.48-1.14 (m, 12H), 1.08-0.94 (m, 6H), 0.84 (d, J = 7.5 Hz, 3H).

Synthesis of 31.13. To a suspension of _MePh3PBr (3.28 g, 9.29 mmol) in anhydrous THF (20 mL) was added t-BuOK (1.04 g, 9.29 mmol) under _N2 at 15 °C. After stirring at 60 °C for 30 min, a solution of 31.12a (350 mg, 0.93 mmol) in anhydrous THF (10 mL) was added dropwise. After stirring at 60 °C for 16 h, the mixture was cooled, poured into ice-water (50 mL), and stirred for 10 min. The aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (100 mL), filtered, concentrated, and purified by flash column (0-10% EtOAc in PE) to give 31.13 (280 mg, 80.4%). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 4.80 (s, 1H), 4.62 (d, J = 2.0 Hz, 1H), 3.47-3.23 (m, 5H), 2.55 (br s, 1H), 2.01 (br d, J = 5.0 Hz, 1H), 1.90-1.57 (m, 11H), 1.49-1.14 (m, 10H), 1.11-0.91 (m, 4H), 0.89 (s, 3H), 0.88-0.84 (m, 2H), 0.82 (d, J = 7.5 Hz, 3H).

Synthesis of 31.14 To a solution of 31.13 (280 mg, 0.747 mmol) in DCM (5 mL) was added _NaHCO (125 mg, 1.49 mmol). m-CPBA (301 mg, 1.49 mmol) was then added to the mixture at ₀ ° C. _{under N.} After stirring at 25° C. for 0.5 h, the mixture was quenched with saturated NaHCO ₍ 20 mL), and the mixture was extracted with DCM (2×20 mL). The combined organic layers were washed with _Na SO (2×20 mL, saturated), brine (2×40 mL), dried _over anhydrous _Na SO , filtered, and concentrated under reduced pressure to give 31.14 (200 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 3.40 (s, 5H), 2.74 (d, J = 4.8 Hz, 1H), 2.65 (d, J = 4.8 Hz, 1H), 2.11-1.81 (m, 2H), 1.80-1.47 (m, 13H), 1.44-1.34 (m, 4H), 1.26 (s, 6H), 1.00 (s, 3H), 0.98-0.91 (m, 2H), 0.81 (d, J=7.5 Hz, 3H).

Synthesis of 31 and 32. To a solution of 31.14 (200 mg, 0.512 mmol) in DMF (3 mL) was added 1H-pyrazole-4-carbonitrile (94.8 mg, 1.02 mmol) and Cs ₂ CO ₃ (498 mg, 1.53 mmol) at 20° C. After stirring at 130° C. for 72 h, water (20 mL) was added to the mixture, and the mixture was extracted with EtOAc (2×30 mL). The organic layer was separated, concentrated, and purified by flash column (0-30% EtOAc in PE) to give 31 and 32 (140 mg). The two diastereomers were purified by SFC (Column: DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 um), Conditions: 0.1% NH ₃ H ₂ O ETOH Start 35% B End 35% B, Gradient time (min) 100% B, Retention time (min), Flow rate (ml/min) 60, Injection 60) to give 31 (Peak 1, Rt=3.513 min, 8.1 mg) and 32 (Peak 2, Rt=3.933 min, 56.9 mg). Compound 31 was further purified by SFC (Column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 um), Conditions: 0.1% NH ₃ H ₂ O ETOH Start B 35% End B 35%, Gradient time (min) 100% B, Retention time (min), Flow rate (ml/min) 60, Injection 60) to give 31 (Peak 1, Rt=1.598 min, 4.2 mg).

31 ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.88 (d, J = 1.5 Hz, 2H), 4.30 (d, J = 13.8 Hz, 1H), 4.03 (d, J = 13.8 Hz, 1H), 3.43-3.35 (m, 5H), 2.53-2.39 (m, 1H), 2.05-1.92 (m, 1H), 1.88-1.80 (m, 1H), 1.77-1.65 (m, 3 H), 1.64-1.47 (m, 3H), 1.46-1.24 (m, 9H), 1.20 (s, 5H), 1.11 (s, 3H), 1.06-0.85 (m, 6H), 0.80 (d, J = 7.5 Hz, 3H), 0.76-0.71 (m, 1H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₈ H ₃₈ N ₃ [M-2H ₂ O-MeOH+H] ⁺ 416.3 found 416.3. SFC 99% de.

32 ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.92 (s, 1H), 7.80 (s, 1H), 4.45-4.35 (m, 1H), 4.30-4.21 (m, 1H), 3.41 (s, 5H), 2.59 (s, 1H), 2.37 (s, 2H), 2.11-1.97 (m, 1H), 1.90- 1.82 (m, 1H), 1.78-1.62 (m, 5H), 1.57-1.54 (m, 7H), 1.48-1.32 (m, 6H), 1.31-1.15 (m, 4H), 1.11 (s, 3H), 1.02 (s, 3H), 0.82 (d, J = 7.4 Hz, 3H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₈ H ₃₈ N ₃ [M-2H ₂ O-CH ₃ OH+H] ⁺ 416.3 found 416.3. SFC 99% de.

Examples 33 and 34: 1-((S)-2-hydroxy-2-((1S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-4,12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (33) and 1-((R)-2-hydroxy-2-((1S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-4,12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile (34).
Synthesis of 33.1 To a solution of t-BuOK (14.6 g, 131 mmol) in THF (250 mL) was added 8.2 (21 g, 65.9 mmol) under _N at 25°C. After stirring for 10 min at 25°C, methyl benzenesulfinate (20.4 g, 131 mmol) was added. The mixture was stirred at 30°C for 0.5 h. The mixture was quenched with _H O (200 mL) and extracted with EtOAc (3 x 200 mL). The organic layer was separated, dried _{over Na} SO , filtered, and concentrated under reduced pressure to give 33.1 (40 g). ^1H NMR (400 MHz, _CDCl3 ) _δH 7.70-7.56 (m, 5H), 3.57-3.55 (m, 1H), 2.47-2.43 (m, 1H), 2.35-1.66 (m, 8H), 1.62-1.29 (m, 12H), 1.28-0.93 (m, 11H).

Synthesis of 33.2 To a mixture of 33.1 (40 g, 90.3 mmol) in xylene (200 mL) was added Na ₂ CO ₃ (143 g, 1.35 mmol) in portions. After stirring at 130° C. under _{N 2} for 12 h, the mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (0-15% EtOAc in PE) to give the product 33.2 (7.8 g, 27%). ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.53-7.51 (dd, J=6 Hz, 1H), 6.03-6.01 (m, 1H), 2.38-2.35 (m, 1H), 1.88-1.50 (m, 10H), 1.49-1.20 (m, 13H), 1.07 (s, 3H), 0.94 (t, J = 7.6 Hz, 3H).

Synthesis of 33.3 To a solution of MeMgBr (24.6 mL, 73.8 mmol, 3 M) in THF (100 mL) was added CuI (14.0 g, 73.8 mmol) at 0° C. After stirring at 0° C. for 1 h, 33.2 (7.8 g, 24.6 mmol) in THF (100 mL) was then added at 0° C. After stirring at 0° C. for 3 h, the mixture was poured into saturated NH ₄ Cl (100 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, and purified by flash column (0-20% EtOAc in PE) to give 33.3 (6.5 g, 79.4%). ^1H NMR (400 MHz, _CDCl3 ) _δH 2.50-2.21 (m, 3H), 1.87-1.44 (m, 13H), 1.43-1.14 (m, 11H), 1.10-1.08 (m, 3H), 1.03 (s, 3H), 0.94 (t, J = 7.2 Hz, 3H).

Synthesis of 33.4 To a solution of 33.3 (6.5 g, 19.5 mmol) and ethyl diazoacetate (11.1 g, 97.5 mmol) in THF (600 mL) was added freshly prepared LDA (48.7 mL, 2 M, 97.5 mmol) at −78° C. After stirring at −78° C. for 2 h, acetic acid (5.85 g, 97.5 mmol) in THF (20 mL) was then added. After stirring at 15° C. for 16 h, the mixture was poured into water (1000 mL). The aqueous phase was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (1500 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated under reduced pressure to give 33.4 (13 g). ^1H NMR (400 MHz, _CDCl3 ) _δH 4.27-4.22 (m, 2H), 2.27-2.20 (m, 1H), 1.99-1.52 (m, 7H), 1.48-1.33 (m, 9H), 1.32-1.06 (m, 14H), 1.03-0.97 (m, 6H), 0.93 (t, J=7.2 Hz, 3H).

Synthesis of 33.5: To a solution of 33.4 (13 g) in DME (300 mL) was added _Rh (OAc ₎ (385 mg, 0.873 mmol) in one portion at 15° C. After stirring for 12 h at 15° C., the mixture was concentrated to give 33.5 (12.5 g). ¹ H NMR (400 MHz, _CDCl ) δ _H 4.48-4.11 (m, 2H), 2.31-1.56 (m, 5H), 1.50-1.33 (m, 7H), 1.31-1.17 (m, 15H), 1.16-1.01 (m, 8H), 0.88-0.85 (m, 3H), 0.78-0.76 (m, 2H).

Synthesis of 33.6 To a mixture of 33.5 (12.5 g, 29.8 mmol) in MeOH (150 mL) was added KOH (9.98 g, 178 mmol). After stirring the mixture at 70° C. for 2 hours, the reaction mixture was concentrated. H ₂ O (300 mL) was then added. The mixture was extracted with EtOAc (3×200 mL). The combined organic phases were washed with brine (2×200 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, and purified by flash column (0-20% EtOAc in PE) to give 33.6 (4.5 g). ^1H NMR (400 MHz, _CDCl3 ) _δH 2.84-2.75 (m, 1H), 2.18-2.12 (m, 2H), 1.88-1.52 (m, 11H), 1.49-1.21 (m, 13H), 1.16 (s, 3H), 1.10-0.97 (m, 5H), 0.93 (t, J = 7.2 Hz; 3H).

Synthesis of 33.7. To a suspension of EtPPh _Br (10.6 g, 28.8 mmol) in anhydrous THF (150 mL) was added t-BuOK (3.23 g, 28.8 mmol) under ^N at 15°C. After stirring at 60°C for 30 min, a solution of 33.6 (2 g, 5.77 mmol) in anhydrous THF (50 mL) was added. The reaction mixture was stirred for 16 h. The mixture was cooled and poured into ice-water (200 mL). The aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine (2 x 100 mL), filtered, concentrated, and purified by flash column (0-10% EtOAc in PE) to give 33.7 (1.3 g). ^1H NMR (400 MHz, _CDCl3 ) _δH 5.18-5.13 (m, 1H), 2.42-2.38 (m, 1H), 2.27-2.00 (m, 2H), 1.88-1.58 (m, 7H), 1.56-1.41 (m, 6H), 1.40-1.16 (m, 13H), 1.09-0.83 (m, 12H).

Synthesis of 33.8 To a solution of 33.7 (1.3 g, 3.62 mmol) in THF (30 mL) was added _BH3.Me2S ( _2.17 mL, 21.7 mmol, 10 M). After stirring at 25°C for 16 h, the mixture was added to ethanol (4.22 mL, 72.4 mmol) at 15°C, followed by aqueous NaOH (14.4 mL, 5.0 M, 72.4 mmol) at 0°C. Hydrogen peroxide (7.24 mL, 10 M, 72.4 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 70°C for 1 h. The mixture was cooled to 15°C, and _Na2S2O3 ( _{100 mL} , saturated aqueous solution) was added. The aqueous solution was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (2 x 50 mL), dried _{over Na2SO4} , filtered, concentrated under reduced pressure, and purified by flash column (0-50% EtOAc in PE) to give 33.8 (1.4 g). ^1H NMR (400 MHz, _CDCl3 ) _δH 4.14-4.05 (m, 1H), 2.04-1.41 (m, 15H), 1.40-1.08 (m, 15H), 1.05-0.77 (m, 13H).

Synthesis of 33.9 To a solution of 33.8 (1.2 g, 3.18 mmol) in DCM (20 mL) was added DMP (2.69 g, 6.36 mmol) at 25° C. After stirring at 25° C. for 30 min, the mixture was quenched with saturated aqueous NaHCO ₃ (30 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with NaS ₂ O ₃ (3×100 mL) and concentrated. The residue was purified by flash column (0-15% EtOAc in PE) to give 33.9a (800 mg). To a solution of 33.9a (800 mg, 2.13 mmol) in MeOH (20 mL) was added MeONa (1.72 g, 31.9 mmol) at 0° C. After stirring at 70° C. for 16 hours, the mixture was then added to saturated NH ₄ Cl (100 mL). The aqueous phase was extracted with EtOAc (2×200 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, and purified by flash column (0-15% EtOAc in PE) to give 33.9 (600 mg). ^1H NMR (400 MHz, _CDCl3 ) _δH 2.28-2.24 (m, 1H), 2.14-2.11 (m, 3H), 2.02-1.97 (m, 1H), 1.96-1.58 (m, 7H) ), 1.50-1.28 (m, 9H), 1.27-1.00 (m, 8H), 0.99 (s, 3H), 0.95-0.82 (m, 10H).

Synthesis of 33.10 To a mixture of MePPh ₃ Br (4.71 g, 13.2 mmol) in THF (50 mL) was added t-BuOK (1.48 g, 13.2 mmol) under N ² at 20° C. After stirring at 60° C. for 30 min, 33.9 (500 mg, 1.33 mmol) in THF (10 mL) was added in one portion below 60° C. The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was quenched with 10% aqueous NH ₄ Cl (100 mL) at 15° C. and extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine (100 mL), filtered, concentrated under reduced pressure, and purified by flash column (0-5% ethyl acetate in PE) to give 33.10 (380 mg, 76.7%). ^1H NMR (400 MHz, _CDCl3 ) _δH 4.79 (s, 1H), 4.62 (s, 1H), 2.04-1.96 (m, 1H), 1.85-1.70 (m, 6H), 1.668- 1.47 (m, 7H), 1.46-1.13 (m, 12H), 1.09-0.89 (m, 11H), 0.88-0.81 (m, 5H).

Synthesis of 33.11 To a solution of 33.10 (190 mg, 0.509 mmol) in DCM (10 mL) was added _NaHCO (84.8 mg, 1.01 mmol) and then m-CPBA (203 mg, 1.01 mmol) at ₀ ° C. under N. After stirring at 25° C. for 0.5 h, the mixture was quenched with saturated _NaHCO (20 mL) and extracted with DCM (2×20 mL ₎ . The organic layer was washed with _{Na SO} (2×20 mL, saturated), brine (2×40 mL), dried _over anhydrous _Na SO , filtered, and concentrated under reduced pressure to give 33.11 (400 mg). ^1H NMR (400 MHz, _CDCl3 ) _δH 2.74-2.64 (m, 2H), 2.04-1.41 (m, 10H), 1.40-1.27 (m, 10H), 1.24 (s, 3H) , 1.21-1.02 (m, 4H), 0.99 (s, 3H), 0.96-0.91 (m, 7H), 0.84-0.75 (m, 5H).

Synthesis of 33 and 34. To a solution of 33.11 (400 mg, 1.02 mmol) in DMF (10 mL) was added 1H-pyrazole-4-carbonitrile (284 mg, 3.06 mmol) and Cs ₂ CO ₃ (997 mg, 3.06 mmol). After stirring at 145° C. for 72 h, the mixture was quenched with water (5 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL x 2), dried _{over Na2SO4} , filtered, concentrated under reduced pressure and purified by column (0-20% EtOAc in PE) to give 33 and 34 (500 mg), which were purified twice by SFC (column DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 um); condition 0.1% _{NH3H2O ETOH} ; start B 40%; end B 40%) to give 33 (peak 1, 17.7 mg, Rt = 3.654 min, 3.5%) and 34 (peak 2, 82.9 mg, Rt = 4.288 min, 16.5%).

33: ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.86 (d, J=2 Hz, 2H), 4.31-4.27 (m, 1H), 4.02-3.99 (m, 1H), 3.10 (s, 1H), 2.45-2.43 (m, 1H), 2.00-1.92 (m, 1 H), 1.82-1.44 (m, 10H), 1.39-1.13 (m, 15H), 1.10 (s, 3H), 1.00-0.82 (m, 8H), 0.79-0.69 (m, 4H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₃₀ H ₄₄ N ₃ [M-2H ₂ O+H] ⁺ 446.4, found 446.4. Analytical SFC 100% de.

34: ^1H NMR (400 MHz, _CDCl3 ), _δH 7.90 (s, 1H), 7.79 (s, 1H), 4.40-4.37 (m, 1H), 4.27-4.23 (m, 1H), 2.41-2.38 (m, 2H), 2.06-2.01 (m, 1H), 1.85-1. 59 (m, 7H), 1.58-1.45 (m, 8H), 1.41-1.16 (m, 12H), 1.10 (s, 3H), 1.07-1.03 (m, 1H), 1.01s (s, 3H), 0.93 (t, J = 7.2 Hz, 3H), 0.82-0.80 (m, 3H). LC-ELSD/MS purity 99%, MS ESI calculated for C ₃₀ H ₄₄ N ₃ [M-2H ₂ O+H] ⁺ 446.4, found 446.4. Analytical SFC 98% de.

Steroid inhibition of TBPS binding. The [ ³⁵ S]-t-butylbicyclophosphorothionate (TBPS) binding assay using rat brain cortical membranes in the presence of 5 mM GABA has been described (Gee et al., J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al., Mol. Pharmacol. 1994, 46, 977-985; Lewin, A.H. et al., Mol. Pharmacol. 1989, 35, 189-194).

Briefly, Sprague-Dawley rats (200-250 g) anesthetized with carbon dioxide were decapitated, and the cortices were rapidly removed. The cortices were homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass/Teflon homogenizer and centrifuged at 1500 x g for 10 minutes at 4°C. The resulting supernatant was centrifuged at 10,000 x g for 20 minutes at 4°C to obtain a P2 pellet. The P2 pellet was resuspended in 200 mM NaCl/50 mM Na-K phosphate pH 7.4 buffer and centrifuged at 10,000 x g for 10 minutes at 4°C. This washing procedure was repeated twice, and the pellet was resuspended in 10 volumes of buffer. Aliquots (100 mL) of membrane suspension are incubated with 3 nM [ ³⁵ S]-TBPS dissolved in dimethyl sulfoxide (DMSO) (0.5% final) and 5 mL aliquots of test drug in the presence of 5 mM GABA. Incubations are brought to a final volume of 1.0 mL with buffer. Nonspecific binding was determined in the presence of 2 mM unlabeled TBPS and ranged from 15 to 25%. After 90 minutes of incubation at room temperature, the assay is terminated by filtration through glass fiber filters (Schleicher and Schuell No. 32) using a cell harvester (Brandel) and rinsing three times with ice-cold buffer. Filter-bound radioactivity is measured by liquid scintillation spectroscopy. Nonlinear curve fitting of the entire data for each drug, averaged for each concentration, is performed using Prism (GraphPad). The data are fit to a partial instead of a full inhibition model if the sum of squares is significantly lower by F-test. Similarly, the data are fit to a two-component instead of a one-component inhibition model if the sum of squares is significantly lower by F-test. The concentration of test compound that produces 50% inhibition of specific binding ( _IC50 ) and the maximum extent of inhibition ( _Imax ) are determined for each experiment using the same model used for the overall data, and then the mean + SEM of each experiment is calculated. Picrotoxin has been shown to robustly inhibit TBPS binding and therefore serves as a positive control for these studies.

Various compounds can be screened to determine their potential as modulators of [ ³⁵ S]-TBPS binding in vitro. These assays can be performed or carried out as described above.

In Table 2 below, A indicates a TBPS IC ₅₀ (μM)<0.1 μM, B indicates a TBPS IC ₅₀ (μM) between 0.1 μM and less than 1.0 μM, and C indicates a TBPS IC ₅₀ (μM) ≧1.0 μM.

Equivalents and Scope In the claims, articles such as "a,""an," and "the" can mean one or more unless indicated to the contrary or otherwise clear from the context. A claim or description including "or" between one or more elements of a group is considered to be satisfied when one, more than one, or all of the group elements are present in, employed in, or otherwise relevant to a given product or process, unless indicated to the contrary or otherwise clear from the context. The invention includes embodiments in which exactly one element of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group elements are present in, employed in, or otherwise relevant to a given product or process.

Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends on the same base claim. Where elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element(s) can be removed from the group. In general, when the invention, or aspects of the invention, are referred to as comprising particular elements and/or features, it should be understood that certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and/or features. For purposes of brevity, those embodiments have not been specifically described verbatim herein. It should also be noted that the terms "comprising" and "containing" are intended to be open-ended and permit the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values expressed as ranges can be extrapolated to any particular value or subrange within the stated range of different embodiments of the invention, down to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. Moreover, any specific embodiment of the present invention within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not explicitly set forth herein, because they are deemed to be known to those of ordinary skill in the art. Any specific embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described in this invention is not intended to be limited to the above description, but rather is as set forth in the appended claims. It will be apparent to those skilled in the art that various changes and modifications to this description can be made without departing from the spirit or scope of the invention, as defined in the following claims.
The present invention provides, for example, the following items.
(Item 1)
Compounds of Formula I:

or a pharmaceutically acceptable salt thereof,
During the ceremony,

represents a single bond or a double bond, provided that when a double bond is present, R ^6a or R ^6b does not exist and R ⁵ Provided that there is no
R ^X halo, -OH, -OR ^Q1 and substituted or unsubstituted alkyl; R ^Q1 is substituted or unsubstituted alkyl;
R ^Y is halo, or substituted or unsubstituted alkyl, or
R ^Y and R ^X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R ⁵ is hydrogen or methyl,
R ²² Each instance of is independently a halogen, —NO ₂ , -CN, -OR ^G.A. , -N(R ^G.A. ) ₂ , -C(=O)R ^G.A. , -C(=O)OR ^G.A. , —OC(═O)R ^G.A. , -OC(=O)OR ^G.A. , -C(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O)R ^G.A. , -OC(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O) OR ^G.A. , -N(R ^G.A. )C(=O)N(R ^G.A. ) ₂ , -SR ^G.A. , -S(=O)R ^G.A. , -S(=O) ₂ R ^G.A. , -S(=O) ₂ OR ^G.A. , -OS(=O) ₂ R ^G.A. , -S(=O) ₂ N (R ^G.A. ) ₂ , -N(R ^G.A. ) S(=O) ₂ R ^G.A. , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ^G.A. Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^G.A. the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a , and R ^12b each independently represents hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -SR ^A1 , -C(=O)R ^A1 , -C(=O)OR ^A1 , -C(=O)SR ^A1 , -C(=O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N (R ^A1 ) ₂ , -N(R ^A1 ) C(=O)R ^A1 , -N(R ^A1 ) C(=NR ^A1 ) R ^A1 , -N(R ^A1 ) C(=O) OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 ) C(=NR ^A1 ) N (R ^A1 ) ₂ , -N(R ^A1 ) S(=O) ₂ R ^A1 , -N(R ^A1 ) S(=O) ₂ OR ^A1 , -N(R ^A1 ) S(=O) ₂ N (R ^A1 ) ₂ , -SC(=O)R ^A1 , -SC(=O)OR ^A1 , -SC(=O)SR ^A1 , -SC(=O)N(R ^A1 ) ₂ , -S(=O) ₂ R ^A1 , -S(=O) ₂ OR ^A1 , or -S(=O) ₂ N (R ^A1 ) ₂ and R ^A1 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ^6a and R ^6b each independently represents hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b is joined to form an oxo (=O) group,
R ^15a , R ^15b , R ^16a , and R ^16b each independently represents hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^C3 , -N(R ^C3 ) ₂ , -SR ^C3 , -C(=O)R ^C3 , -C(=O)OR ^C3 , -C(=O)SR ^C3 , -C(=O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , -OC(=O)OR ^C3 , -OC(=O)N(R ^C3 ) ₂ , -OC(=O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N (R ^C3 ) ₂ , -N(R ^C3 ) C(=O)R ^C3 , -N(R ^C3 ) C(=NR ^C3 ) R ^C3 , -N(R ^C3 ) C(=O) OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 ) C(=NR ^C3 ) N (R ^C3 ) ₂ , -N(R ^C3 ) S(=O) ₂ R ^C3 , -N(R ^C3 ) S(=O) ₂ OR ^C3 , -N(R ^C3 ) S(=O) ₂ N (R ^C3 ) ₂ , -SC(=O)R ^C3 , -SC(=O)OR ^C3 , -SC(=O)SR ^C3 , -SC(=O)N(R ^C3 ) ₂ , -S(=O) ₂ R ^C3 , -S(=O) ₂ OR ^C3 , or -S(=O) ₂ N (R ^C3 ) ₂ and R ^C3 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; ^C3 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen, or substituted or unsubstituted alkyl;
n is 0, 1, 2, or 3;
The compound or a pharmaceutically acceptable salt thereof, wherein t is 2 or 3.
(Item 2)
Item 1. The compound according to item 1, wherein t is 2.
(Item 3)
Compound of Formula II:

or a pharmaceutically acceptable salt thereof,
During the ceremony,

represents a single bond or a double bond, provided that when a double bond is present, R ^6a or R ^6b does not exist and R ⁵ Provided that there is no
R ^X halo, -OH, -OR ^Q1 and substituted or unsubstituted alkyl; R ^Q1 is substituted or unsubstituted alkyl;
R ^Y is halo, or substituted or unsubstituted alkyl, or
R ^Y and R ^X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R ⁵ is hydrogen or methyl,
R ²² Each instance of is independently a halogen, —NO ₂ , -CN, -OR ^G.A. , -N(R ^G.A. ) ₂ , -C(=O)R ^G.A. , -C(=O)OR ^G.A. , -OC(=O)R ^G.A. , -OC(=O)OR ^G.A. , -C(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O)R ^G.A. , -OC(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O) OR ^G.A. , -N(R ^G.A. )C(=O)N(R ^G.A. ) ₂ , -SR ^G.A. , -S(=O)R ^G.A. , -S(=O) ₂ R ^G.A. , -S(=O) ₂ OR ^G.A. , -OS(=O) ₂ R ^G.A. , -S(=O) ₂ N (R ^G.A. ) ₂ , -N(R ^G.A. ) S(=O) ₂ R ^G.A. , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ^G.A. Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^G.A. groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a , and R ^12b each independently represents hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -SR ^A1 , -C(=O)R ^A1 , -C(=O)OR ^A1 , -C(=O)SR ^A1 , -C(=O)N(R ^A1 ) ₂ , -OC(=O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N (R ^A1 ) ₂ , -N(R ^A1 ) C(=O)R ^A1 , -N(R ^A1 ) C(=NR ^A1 ) R ^A1 , -N(R ^A1 ) C(=O) OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 ) C(=NR ^A1 ) N (R ^A1 ) ₂ , -N(R ^A1 ) S(=O) ₂ R ^A1 , -N(R ^A1 ) S(=O) ₂ OR ^A1 , -N(R ^A1 ) S(=O) ₂ N (R ^A1 ) ₂ , -SC(=O)R ^A1 , -SC(=O)OR ^A1 , -SC(=O)SR ^A1 , -SC(=O)N(R ^A1 ) ₂ , -S(=O) ₂ R ^A1 , -S(=O) ₂ OR ^A1 , or -S(=O) ₂ N (R ^A1 ) ₂ and R ^A1 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ^6a and R ^6b each independently represents hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b is joined to form an oxo (=O) group,
R ^15a , R ^15b , R ^16a , and R ^16b each independently represents hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^C3 , -N(R ^C3 ) ₂ , -SR ^C3 , -C(=O)R ^C3 , -C(=O)OR ^C3 , -C(=O)SR ^C3 , -C(=O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , -OC(=O)OR ^C3 , -OC(=O)N(R ^C3 ) ₂ , -OC(=O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N (R ^C3 ) ₂ , -N(R ^C3 ) C(=O)R ^C3 , -N(R ^C3 ) C(=NR ^C3 ) R ^C3 , -N(R ^C3 ) C(=O) OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 ) C(=NR ^C3 ) N (R ^C3 ) ₂ , -N(R ^C3 ) S(=O) ₂ R ^C3 , -N(R ^C3 ) S(=O) ₂ OR ^C3 , -N(R ^C3 ) S(=O) ₂ N (R ^C3 ) ₂ , -SC(=O)R ^C3 , -SC(=O)OR ^C3 , -SC(=O)SR ^C3 , -SC(=O)N(R ^C3 ) ₂ , -S(=O) ₂ R ^C3 , -S(=O) ₂ OR ^C3 , or -S(=O) ₂ N (R ^C3 ) ₂ and R ^C3 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; ^C3 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen, or substituted or unsubstituted alkyl;
R ¹⁸ is substituted or unsubstituted alkyl;
n is 0, 1, 2, or 3, provided that R ⁵ is hydrogen, R ¹⁸ Ga-CH ₃ or a pharmaceutically acceptable salt thereof, which is not
(Item 4)
The compound of formula II is a compound of formula IIIa or IIIb:

or a pharmaceutically acceptable salt thereof.
(Item 5)
Compound of Formula V:

or a pharmaceutically acceptable salt thereof,
During the ceremony,

represents a single bond or a double bond, provided that when a double bond is present, R ^6a or R ^6b does not exist and R ⁵ Provided that there is no
R ^X halo, -OH, -OR ^Q1 and substituted or unsubstituted alkyl; R ^Q1 is substituted or unsubstituted alkyl;
R ^Y is halo, or substituted or unsubstituted alkyl, or
R ^Y and R ^X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R ⁵ is hydrogen or methyl,
R ²² Each instance of is independently a halogen, —NO ₂ , -CN, -OR ^G.A. , -N(R ^G.A. ) ₂ , -C(=O)R ^G.A. , -C(=O)OR ^G.A. , —OC(═O)R ^G.A. , -OC(=O)OR ^G.A. , -C(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O)R ^G.A. , -OC(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O) OR ^G.A. , -N(R ^G.A. )C(=O)N(R ^G.A. ) ₂ , -SR ^G.A. , -S(=O)R ^G.A. , -S(=O) ₂ R ^G.A. , -S(=O) ₂ OR ^G.A. , -OS(=O) ₂ R ^G.A. , -S(=O) ₂ N (R ^G.A. ) ₂ , -N(R ^G.A. ) S(=O) ₂ R ^G.A. , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ^G.A. Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^G.A. groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a , and R ^12b each independently represents hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -SR ^A1 , -C(=O)R ^A1 , -C(=O)OR ^A1 , -C(=O)SR ^A1 , -C(=O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N (R ^A1 ) ₂ , -N(R ^A1 ) C(=O)R ^A1 , -N(R ^A1 ) C(=NR ^A1 ) R ^A1 , -N(R ^A1 ) C(=O) OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 ) C(=NR ^A1 ) N (R ^A1 ) ₂ , -N(R ^A1 ) S(=O) ₂ R ^A1 , -N(R ^A1 ) S(=O) ₂ OR ^A1 , -N(R ^A1 ) S(=O) ₂ N (R ^A1 ) ₂ , -SC(=O)R ^A1 , -SC(=O)OR ^A1 , -SC(=O)SR ^A1 , -SC(=O)N(R ^A1 ) ₂ , -S(=O) ₂ R ^A1 , -S(=O) ₂ OR ^A1 , or -S(=O) ₂ N (R ^A1 ) ₂ and R ^A1 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ^6a and R ^6b each independently represents hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b is joined to form an oxo (=O) group,
R ^15a or R ^15b each independently represents hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^C3 , -N(R ^C3 ) ₂ , -SR ^C3 , -C(=O)R ^C3 , -C(=O)OR ^C3 , -C(=O)SR ^C3 , -C(=O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , -OC(=O)OR ^C3 , -OC(=O)N(R ^C3 ) ₂ , -OC(=O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N (R ^C3 ) ₂ , -N(R ^C3 ) C(=O)R ^C3 , -N(R ^C3 ) C(=NR ^C3 ) R ^C3 , -N(R ^C3 ) C(=O) OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 ) C(=NR ^C3 ) N (R ^C3 ) ₂ , -N(R ^C3 ) S(=O) ₂ R ^C3 , -N(R ^C3 ) S(=O) ₂ OR ^C3 , -N(R ^C3 ) S(=O) ₂ N (R ^C3 ) ₂ , -SC(=O)R ^C3 , -SC(=O)OR ^C3 , -SC(=O)SR ^C3 , -SC(=O)N(R ^C3 ) ₂ , -S(=O) ₂ R ^C3 , -S(=O) ₂ OR ^C3 , or -S(=O) ₂ N (R ^C3 ) ₂ and R ^C3 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; ^C3 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen, or substituted or unsubstituted alkyl;
The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
(Item 6)
Compounds of Formula VIa or VIb:

or a pharmaceutically acceptable salt thereof,
During the ceremony,

represents a single bond or a double bond, provided that when a double bond is present, R ^6a or R ^6b does not exist and R ⁵ Provided that there is no
R ^X halo, -OH, -OR ^Q1 and substituted or unsubstituted alkyl; R ^Q1 is substituted or unsubstituted alkyl;
R ^Y is halo, or substituted or unsubstituted alkyl, or
R ^Y and R ^X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R ⁵ is hydrogen or methyl,
R ²² Each instance of is independently a halogen, —NO ₂ , -CN, -OR ^G.A. , -N(R ^G.A. ) ₂ , -C(=O)R ^G.A. , -C(=O)OR ^G.A. , —OC(═O)R ^G.A. , -OC(=O)OR ^G.A. , -C(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O)R ^G.A. , -OC(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O) OR ^G.A. , -N(R ^G.A. )C(=O)N(R ^G.A. ) ₂ , -SR ^G.A. , -S(=O)R ^G.A. , -S(=O) ₂ R ^G.A. , -S(=O) ₂ OR ^G.A. , -OS(=O) ₂ R ^G.A. , -S(=O) ₂ N (R ^G.A. ) ₂ , -N(R ^G.A. ) S(=O) ₂ R ^G.A. , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ^G.A. Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^G.A. groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a , and R ^12b each independently represents hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -SR ^A1 , -C(=O)R ^A1 , -C(=O)OR ^A1 , -C(=O)SR ^A1 , -C(=O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N (R ^A1 ) ₂ , -N(R ^A1 ) C(=O)R ^A1 , -N(R ^A1 ) C(=NR ^A1 ) R ^A1 , -N(R ^A1 ) C(=O) OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 ) C(=NR ^A1 ) N (R ^A1 ) ₂ , -N(R ^A1 ) S(=O) ₂ R ^A1 , -N(R ^A1 ) S(=O) ₂ OR ^A1 , -N(R ^A1 ) S(=O) ₂ N (R ^A1 ) ₂ , -SC(=O)R ^A1 , -SC(=O)OR ^A1 , -SC(=O)SR ^A1 , -SC(=O)N(R ^A1 ) ₂ , -S(=O) ₂ R ^A1 , -S(=O) ₂ OR ^A1 , or -S(=O) ₂ N (R ^A1 ) ₂ and R ^A1 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups, together with said intervening atoms, form a substituted or unsubstituted heterocyclic ring;
R ^6a and R ^6b each independently represents hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b is joined to form an oxo (=O) group,
R ^15a , R ^15b , R ^16a , and R ^16b each independently represents hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^C3 , -N(R ^C3 ) ₂ , -SR ^C3 , -C(=O)R ^C3 , -C(=O)OR ^C3 , -C(=O)SR ^C3 , -C(=O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , -OC(=O)OR ^C3 , -OC(=O)N(R ^C3 ) ₂ , -OC(=O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N (R ^C3 ) ₂ , -N(R ^C3 ) C(=O)R ^C3 , -N(R ^C3 ) C(=NR ^C3 ) R ^C3 , -N(R ^C3 ) C(=O) OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 ) C(=NR ^C3 ) N (R ^C3 ) ₂ , -N(R ^C3 ) S(=O) ₂ R ^C3 , -N(R ^C3 ) S(=O) ₂ OR ^C3 , -N(R ^C3 ) S(=O) ₂ N (R ^C3 ) ₂ , -SC(=O)R ^C3 , -SC(=O)OR ^C3 , -SC(=O)SR ^C3 , -SC(=O)N(R ^C3 ) ₂ , -S(=O) ₂ R ^C3 , -S(=O) ₂ OR ^C3 , or -S(=O) ₂ N (R ^C3 ) ₂ and R ^C3 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; ^C3 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen, or substituted or unsubstituted alkyl;
r is 2 or 3;
p is 2 or 3;
The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
(Item 7)
7. The compound according to claim 6, wherein p is 2.
(Item 8)
7. The compound according to claim 6, wherein r is 2.
(Item 9)
Compound of Formula VII:
or a pharmaceutically acceptable salt thereof,
During the ceremony,

represents a single bond or a double bond, provided that when a double bond is present, R ^6a or R ^6b does not exist and R ⁵ Provided that there is no
R ^X halo, -OH, -OR ^Q1 and substituted or unsubstituted alkyl; R ^Q1 is substituted or unsubstituted alkyl;
R ^Y is halo, or substituted or unsubstituted alkyl, or
R ^Y and R ^X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R ⁵ is hydrogen or methyl,
R ²² Each instance of is independently a halogen, —NO ₂ , -CN, -OR ^G.A. , -N(R ^G.A. ) ₂ , -C(=O)R ^G.A. , -C(=O)OR ^G.A. , —OC(═O)R ^G.A. , -OC(=O)OR ^G.A. , -C(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O)R ^G.A. , -OC(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O) OR ^G.A. , -N(R ^G.A. )C(=O)N(R ^G.A. ) ₂ , -SR ^G.A. , -S(=O)R ^G.A. , -S(=O) ₂ R ^G.A. , -S(=O) ₂ OR ^G.A. , -OS(=O) ₂ R ^G.A. , -S(=O) ₂ N (R ^G.A. ) ₂ , -N(R ^G.A. ) S(=O) ₂ R ^G.A. , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ^G.A. Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^G.A. groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a , and R ^12b each independently represents hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -SR ^A1 , -C(=O)R ^A1 , -C(=O)OR ^A1 , -C(=O)SR ^A1 , -C(=O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N (R ^A1 ) ₂ , -N(R ^A1 ) C(=O)R ^A1 , -N(R ^A1 ) C(=NR ^A1 ) R ^A1 , -N(R ^A1 ) C(=O) OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 ) C(=NR ^A1 ) N (R ^A1 ) ₂ , -N(R ^A1 ) S(=O) ₂ R ^A1 , -N(R ^A1 ) S(=O) ₂ OR ^A1 , -N(R ^A1 ) S(=O) ₂ N (R ^A1 ) ₂ , -SC(=O)R ^A1 , -SC(=O)OR ^A1 , -SC(=O)SR ^A1 , -SC(=O)N(R ^A1 ) ₂ , -S(=O) ₂ R ^A1 , -S(=O) ₂ OR ^A1 , or -S(=O) ₂ N (R ^A1 ) ₂ and R ^A1 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ^6a and R ^6b each independently represents hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b is joined to form an oxo (=O) group,
R ^15a , R ^15b , R ^16a , and R ^16b each independently represents hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^C3 , -N(R ^C3 ) ₂ , -SR ^C3 , -C(=O)R ^C3 , -C(=O)OR ^C3 , -C(=O)SR ^C3 , -C(=O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , -OC(=O)OR ^C3 , -OC(=O)N(R ^C3 ) ₂ , -OC(=O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N (R ^C3 ) ₂ , -N(R ^C3 ) C(=O)R ^C3 , -N(R ^C3 ) C(=NR ^C3 ) R ^C3 , -N(R ^C3 ) C(=O) OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 ) C(=NR ^C3 ) N (R ^C3 ) ₂ , -N(R ^C3 ) S(=O) ₂ R ^C3 , -N(R ^C3 ) S(=O) ₂ OR ^C3 , -N(R ^C3 ) S(=O) ₂ N (R ^C3 ) ₂ , -SC(=O)R ^C3 , -SC(=O)OR ^C3 , -SC(=O)SR ^C3 , -SC(=O)N(R ^C3 ) ₂ , -S(=O) ₂ R ^C3 , -S(=O) ₂ OR ^C3 , or -S(=O) ₂ N (R ^C3 ) ₂ and R ^C3 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; ^C3 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen, or substituted or unsubstituted alkyl;
The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
(Item 10)
Compound of Formula VIII:

or a pharmaceutically acceptable salt thereof,
During the ceremony,

represents a single bond or a double bond, provided that when a double bond is present, R ^6a or R ^6b does not exist and R ⁵ Provided that there is no
R ^X halo, -OH, -OR ^Q1 and substituted or unsubstituted alkyl; R ^Q1 is substituted or unsubstituted alkyl;
R ^Y is halo, or substituted or unsubstituted alkyl, or
R ^Y and R ^X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R ⁵ is hydrogen or methyl,
R ²² Each instance of is independently a halogen, —NO ₂ , -CN, -OR ^G.A. , -N(R ^G.A. ) ₂ , -C(=O)R ^G.A. , -C(=O)OR ^G.A. , —OC(═O)R ^G.A. , -OC(=O)OR ^G.A. , -C(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O)R ^G.A. , -OC(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O) OR ^G.A. , -N(R ^G.A. )C(=O)N(R ^G.A. ) ₂ , -SR ^G.A. , -S(=O)R ^G.A. , -S(=O) ₂ R ^G.A. , -S(=O) ₂ OR ^G.A. , -OS(=O) ₂ R ^G.A. , -S(=O) ₂ N (R ^G.A. ) ₂ , -N(R ^G.A. ) S(=O) ₂ R ^G.A. , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ^G.A. Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^G.A. groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a , and R ^12b each independently represents hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -SR ^A1 , -C(=O)R ^A1 , -C(=O)OR ^A1 , -C(=O)SR ^A1 , -C(=O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N (R ^A1 ) ₂ , -N(R ^A1 ) C(=O)R ^A1 , -N(R ^A1 ) C(=NR ^A1 ) R ^A1 , -N(R ^A1 ) C(=O) OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 ) C(=NR ^A1 ) N (R ^A1 ) ₂ , -N(R ^A1 ) S(=O) ₂ R ^A1 , -N(R ^A1 ) S(=O) ₂ OR ^A1 , -N(R ^A1 ) S(=O) ₂ N (R ^A1 ) ₂ , -SC(=O)R ^A1 , -SC(=O)OR ^A1 , -SC(=O)SR ^A1 , -SC(=O)N(R ^A1 ) ₂ , -S(=O) ₂ R ^A1 , -S(=O) ₂ OR ^A1 , or -S(=O) ₂ N (R ^A1 ) ₂ and R ^A1 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups, together with said intervening atoms, form a substituted or unsubstituted heterocyclic ring;
R ^6a and R ^6b each independently represents hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b is joined to form an oxo (=O) group,
R ^15a , R ^15b , R ^16a , and R ^16b each independently represents hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^C3 , -N(R ^C3 ) ₂ , -SR ^C3 , -C(=O)R ^C3 , -C(=O)OR ^C3 , -C(=O)SR ^C3 , -C(=O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , -OC(=O)OR ^C3 , -OC(=O)N(R ^C3 ) ₂ , -OC(=O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N (R ^C3 ) ₂ , -N(R ^C3 ) C(=O)R ^C3 , -N(R ^C3 ) C(=NR ^C3 ) R ^C3 , -N(R ^C3 ) C(=O) OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 ) C(=NR ^C3 ) N (R ^C3 ) ₂ , -N(R ^C3 ) S(=O) ₂ R ^C3 , -N(R ^C3 ) S(=O) ₂ OR ^C3 , -N(R ^C3 ) S(=O) ₂ N (R ^C3 ) ₂ , -SC(=O)R ^C3 , -SC(=O)OR ^C3 , -SC(=O)SR ^C3 , -SC(=O)N(R ^C3 ) ₂ , -S(=O) ₂ R ^C3 , -S(=O) ₂ OR ^C3 , or -S(=O) ₂ N (R ^C3 ) ₂ and R ^C3 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; ^C3 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen, or substituted or unsubstituted alkyl;
s is 2,
The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
(Item 11)
Compound of Formula IX:


or a pharmaceutically acceptable salt thereof,
During the ceremony,
R ^X halo, -OH, -OR ^Q1 and substituted or unsubstituted alkyl; R ^Q1 is substituted or unsubstituted alkyl;
R ^Y is halo, or substituted or unsubstituted alkyl, or
R ^Y and R ^X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R ⁵ is hydrogen or methyl,
R ²² Each instance of is independently a halogen, —NO ₂ , -CN, -OR ^G.A. , -N(R ^G.A. ) ₂ , -C(=O)R ^G.A. , -C(=O)OR ^G.A. , —OC(═O)R ^G.A. , -OC(=O)OR ^G.A. , -C(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O)R ^G.A. , -OC(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O) OR ^G.A. , -N(R ^G.A. )C(=O)N(R ^G.A. ) ₂ , -SR ^G.A. , -S(=O)R ^G.A. , -S(=O) ₂ R ^G.A. , -S(=O) ₂ OR ^G.A. , -OS(=O) ₂ R ^G.A. , -S(=O) ₂ N (R ^G.A. ) ₂ , -N(R ^G.A. ) S(=O) ₂ R ^G.A. , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ^G.A. Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^G.A. groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a , and R ^12b each independently represents hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -SR ^A1 , -C(=O)R ^A1 , -C(=O)OR ^A1 , -C(=O)SR ^A1 , -C(=O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N (R ^A1 ) ₂ , -N(R ^A1 ) C(=O)R ^A1 , -N(R ^A1 ) C(=NR ^A1 ) R ^A1 , -N(R ^A1 ) C(=O) OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 ) C(=NR ^A1 ) N (R ^A1 ) ₂ , -N(R ^A1 ) S(=O) ₂ R ^A1 , -N(R ^A1 ) S(=O) ₂ OR ^A1 , -N(R ^A1 ) S(=O) ₂ N (R ^A1 ) ₂ , -SC(=O)R ^A1 , -SC(=O)OR ^A1 , -SC(=O)SR ^A1 , -SC(=O)N(R ^A1 ) ₂ , -S(=O) ₂ R ^A1 , -S(=O) ₂ OR ^A1 , or -S(=O) ₂ N (R ^A1 ) ₂ and R ^A1 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups, together with said intervening atoms, form a substituted or unsubstituted heterocyclic ring;
R ^15a , R ^15b , R ^16a , and R ^16b each independently represents hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^C3 , -N(R ^C3 ) ₂ , -SR ^C3 , -C(=O)R ^C3 , -C(=O)OR ^C3 , -C(=O)SR ^C3 , -C(=O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , -OC(=O)OR ^C3 , -OC(=O)N(R ^C3 ) ₂ , -OC(=O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N (R ^C3 ) ₂ , -N(R ^C3 ) C(=O)R ^C3 , -N(R ^C3 ) C(=NR ^C3 ) R ^C3 , -N(R ^C3 ) C(=O) OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 ) C(=NR ^C3 ) N (R ^C3 ) ₂ , -N(R ^C3 ) S(=O) ₂ R ^C3 , -N(R ^C3 ) S(=O) ₂ OR ^C3 , -N(R ^C3 ) S(=O) ₂ N (R ^C3 ) ₂ , -SC(=O)R ^C3 , -SC(=O)OR ^C3 , -SC(=O)SR ^C3 , -SC(=O)N(R ^C3 ) ₂ , -S(=O) ₂ R ^C3 , -S(=O) ₂ OR ^C3 , or -S(=O) ₂ N (R ^C3 ) ₂ and R ^C3 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; ^C3 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen, or substituted or unsubstituted alkyl;
The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
(Item 12)
Compound of Formula X:

or a pharmaceutically acceptable salt thereof,
During the ceremony,

represents a single bond or a double bond, provided that when a double bond is present, R ^6a or R ^6b does not exist and R ⁵ Provided that there is no
R ^X halo, -OH, -OR ^Q1 and substituted or unsubstituted alkyl; R ^Q1 is substituted or unsubstituted alkyl;
R ^Y is halo, or substituted or unsubstituted alkyl, or
R ^Y and R ^X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl;
R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R ⁵ is hydrogen or methyl,
R ²² Each instance of is independently a halogen, —NO ₂ , -CN, -OR ^G.A. , -N(R ^G.A. ) ₂ , -C(=O)R ^G.A. , -C(=O)OR ^G.A. , —OC(═O)R ^G.A. , -OC(=O)OR ^G.A. , -C(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O)R ^G.A. , -OC(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O) OR ^G.A. , -N(R ^G.A. )C(=O)N(R ^G.A. ) ₂ , -SR ^G.A. , -S(=O)R ^G.A. , -S(=O) ₂ R ^G.A. , -S(=O) ₂ OR ^G.A. , -OS(=O) ₂ R ^G.A. , -S(=O) ₂ N (R ^G.A. ) ₂ , -N(R ^G.A. ) S(=O) ₂ R ^G.A. , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ^G.A. Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R ^G.A. groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a , and R ^12b each independently represents hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -N(R ^A1 ) ₂ , -SR ^A1 , -C(=O)R ^A1 , -C(=O)OR ^A1 , -C(=O)SR ^A1 , -C(=O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N (R ^A1 ) ₂ , -N(R ^A1 ) C(=O)R ^A1 , -N(R ^A1 ) C(=NR ^A1 ) R ^A1 , -N(R ^A1 ) C(=O) OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 ) C(=NR ^A1 ) N (R ^A1 ) ₂ , -N(R ^A1 ) S(=O) ₂ R ^A1 , -N(R ^A1 ) S(=O) ₂ OR ^A1 , -N(R ^A1 ) S(=O) ₂ N (R ^A1 ) ₂ , -SC(=O)R ^A1 , -SC(=O)OR ^A1 , -SC(=O)SR ^A1 , -SC(=O)N(R ^A1 ) ₂ , -S(=O) ₂ R ^A1 , -S(=O) ₂ OR ^A1 , or -S(=O) ₂ N (R ^A1 ) ₂ and R ^A1 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} Alkynyl, substituted or unsubstituted C _{3 to 6} carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups, together with said intervening atoms, form a substituted or unsubstituted heterocyclic ring;
R ^6a and R ^6b each independently represents hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b is joined to form an oxo (=O) group,
R ^15a , R ^15b , R ^16a , and R ^16b each independently represents hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^C3 , -N(R ^C3 ) ₂ , -SR ^C3 , -C(=O)R ^C3 , -C(=O)OR ^C3 , -C(=O)SR ^C3 , -C(=O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , -OC(=O)OR ^C3 , -OC(=O)N(R ^C3 ) ₂ , -OC(=O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N (R ^C3 ) ₂ , -N(R ^C3 ) C(=O)R ^C3 , -N(R ^C3 ) C(=NR ^C3 ) R ^C3 , -N(R ^C3 ) C(=O) OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 ) C(=NR ^C3 ) N (R ^C3 ) ₂ , -N(R ^C3 ) S(=O) ₂ R ^C3 , -N(R ^C3 ) S(=O) ₂ OR ^C3 , -N(R ^C3 ) S(=O) ₂ N (R ^C3 ) ₂ , -SC(=O)R ^C3 , -SC(=O)OR ^C3 , -SC(=O)SR ^C3 , -SC(=O)N(R ^C3 ) ₂ , -S(=O) ₂ R ^C3 , -S(=O) ₂ OR ^C3 , or -S(=O) ₂ N (R ^C3 ) ₂ and R ^C3 Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{2 to 6} Alkenyl, substituted or unsubstituted C _{2 to 6} or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; ^C3 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen, or substituted or unsubstituted alkyl;
q is 2,
The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
(Item 13)
R ^1a and R ^1b and are both hydrogen.
(Item 14)
R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a , and R ^12b 14. The compound according to any one of items 1 to 13, wherein is hydrogen.
(Item 15)
R ^6a and R ^6b and are both hydrogen.
(Item 16)
R ^15a and R ^15b 16. The compound of any one of items 1 to 15, wherein each of is independently hydrogen or substituted or unsubstituted alkyl.
(Item 17)
R ^15a and R ^15b 17. The compound according to any one of items 1 to 16, wherein each of is independently hydrogen or methyl.
(Item 18)
R ^15a and R ^15b and are both hydrogen.
(Item 19)
R ^16a and R ^16b and are both hydrogen.
(Item 20)
R ³ is a substituted or unsubstituted C _{1 to 6} 20. The compound according to any one of items 1 to 19, wherein the aryl group is alkyl.
(Item 21)
R ³ 21. The compound according to any one of items 1 to 20, wherein is methyl, ethyl, or n-propyl.
(Item 22)
R ¹⁹ is hydrogen or unsubstituted C _{1 to 6} 22. The compound according to any one of items 1 to 21, wherein the aryl group is alkyl.
(Item 23)
R ^X 23. The compound according to any one of items 1 to 22, wherein is —OH.
(Item 24)
R ^Y is unsubstituted C _{1 to 3} 24. The compound according to any one of items 1 to 23, wherein the aryl group is alkyl.
(Item 25)
R ²² independently for each occurrence a halogen, —CN, —OR ^G.A. , -N(R ^G.A. ) ₂ , substituted or unsubstituted C _{1 to 6} Alkyl, substituted or unsubstituted C _{3 to 6} carbosilyl, R ^G.A. Each instance of is independently hydrogen, substituted or unsubstituted C _{1 to 6} Alkyl, or substituted or unsubstituted C _{3 to 6} 25. The compound according to any one of items 1 to 24, which is carbosilyl.
(Item 26)
R ⁵ 26. The compound according to any one of items 1 to 3 and 5 to 25, wherein is hydrogen in the alpha or beta configuration.
(Item 27)
The compound is



27. The compound according to any one of items 1 to 26, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
(Item 28)
28. A pharmaceutical composition comprising a compound according to any one of items 1 to 27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
(Item 29)
GABA _A A method for modulating a receptor in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 28.
(Item 30)
28. A method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 28.

Claims (124)

Compounds of formula (I):

or a pharmaceutically acceptable salt thereof,
During the ceremony,

represents a single or double bond, provided that when a double bond is present, one of R ^6a or R ^6b is absent and R ⁵ is absent;
R ^X is selected from the group consisting of halo, —OH, —OR ^Q1 , and substituted or unsubstituted alkyl, and R ^Q1 is substituted or unsubstituted alkyl;
R ^Y is halo, or substituted or unsubstituted alkyl;
^R3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
^R5 is hydrogen or methyl;
Each instance of R ²² is independently halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —OC(═O)R ^GA , —OC(═O)OR ^GA , —C(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)R ^GA , —OC(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)OR ^GA , —N(R ^GA )C(═O)N(R ^GA ) ₂ , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ OR ^GA , —OS(═O) ₂ R ^GA , —S(═O) ₂ N(R ^GA ) ₂ , —N(R ^GA )S(═O) ₂ R ^GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R ^GA is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two ^RGA groups together with intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
Each of R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a and R ^12b is independently hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^A1 , —N(R ^A1 ) ₂ , —SR ^A1 , —C(═O)R ^A1 , —C(═O)OR ^A1 , —C(═O)SR ^A1 , —C(═O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N(R ^A1 ) ₂ , -N(R ^A1 )C(=O)R ^A1 , -N(R ^A1 )C(=NR ^A1 )R ^A1 , -N(R ^A1 )C(=O)OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 )C(=NR ^A1 )N(R ^A1 ) ₂ , -N(R ^A1 )S(=O) ₂ R ^A1 , —N(R ^A1 )S(═O) ₂ OR ^A1 , —N(R ^A1 )S(═O) ₂ N(R ^A1 ) ₂ , —SC(═O)R ^A1 , —SC(═O)OR ^A1 , —SC(═O)SR ^A1 , —SC(═O)N(R ^A1 ) ₂ , —S(═O) ₂ R ^A1 , —S(═O) ₂ OR ^A1 , or —S(═O) ₂ N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, or substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
each of R ^6a and R ^6b is independently selected from the group consisting of hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b are joined to form an oxo (═O) group;
Each of R ^15a , R ^15b , R ^16a and R ^16b is independently hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^C3 , —N(R ^C3 ) ₂ , —SR ^C3 , —C(═O)R ^C3 , —C(═O)OR ^C3 , —C(═O)SR ^C3 , —C(═O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , —OC(═O)OR ^C3 , —OC(═O)N(R ^C3 ) ₂ , —OC(═O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N(R ^C3 ) ₂ , -N(R ^C3 )C(=O)R ^C3 , -N(R ^C3 )C(=NR ^C3 )R ^C3 , -N(R ^C3 )C(=O)OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 )C(=NR ^C3 )N(R ^C3 ) ₂ , -N(R ^C3 )S(=O) ₂ R ^C3 , -N(R ^C3 )S(=O) ₂ OR ^C3 , -N(R ^C3 )S(=O) ₂ N(R ^C3 ) ₂ , —SC(═O)R ^C3 , —SC(═O)OR ^C3 , —SC(═O)SR ^C3 , —SC(═O)N(R ^C3 ) ₂ , —S(═O) _2R ^C3 , —S(═O) _2OR ^C3 , or —S(═O) _2N (R ^C3 ) ₂ , wherein each instance of R ^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; or two R ^{the C3} group together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen or substituted or unsubstituted alkyl;
n is 0, 1, 2, or 3;
The compound, or a pharmaceutically acceptable salt thereof, wherein t is 2. Each instance of R ²² is independently halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —OC(═O)R ^GA , —OC(═O)OR ^GA , —C(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)R ^GA , —OC(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)OR ^GA , —N(R ^GA )C(═O)N(R ^GA ) ₂ , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ 2. The compound or pharmaceutically acceptable salt of claim 1, wherein OR ^GA , -OS(=O) ₂ R ^GA , -S(=O) ₂ N(R ^GA ) ₂ , -N( R ^GA )S(=O) _{2 R GA , unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, and unsubstituted heteroaryl, wherein each instance of R GA is hydrogen, unsubstituted C 1-6 alkyl} , ^{unsubstituted} C 2-6 ^alkenyl , _{unsubstituted} C 2-6 _{alkynyl ,} unsubstituted C 3-6 carbocyclyl, unsubstituted 3-6 membered heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl . 2. The compound or pharmaceutically acceptable salt of claim 1 , wherein ^R3 is substituted or unsubstituted _C1-6 alkyl. 2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ^R3 is _{C1-3 alkyl optionally substituted with C1-3 alkoxy} . _5. The compound or pharmaceutically acceptable salt of claim 4, wherein ^R3 is methyl, ethyl, propyl, n-propyl, butyl, _{-CH2OCH3 ,} or _{-CH2OCH2CH3 .} 2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R ¹⁹ is hydrogen or unsubstituted C _1-3 alkyl. 7. The compound or pharmaceutically acceptable salt of claim 6, wherein R ¹⁹ is hydrogen or methyl. 2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R ^15a and R ^15b is independently hydrogen or substituted or unsubstituted alkyl. 9. The compound or pharmaceutically acceptable salt of claim 8, wherein each of R ^15a and R ^15b is independently hydrogen or methyl. 10. The compound or pharmaceutically acceptable salt of claim 9, wherein each of R ^15a and R ^15b is hydrogen. 2. The compound or pharmaceutically acceptable salt of claim 1 , wherein each of R ^16a and R ^16b is hydrogen.
2. The compound or pharmaceutically acceptable salt of claim 1 , wherein R is a single bond and R ⁵ is hydrogen or methyl.
13. The compound or pharmaceutically acceptable salt of claim 12 , wherein R is a single bond and ^R5 is hydrogen.
2. The compound or pharmaceutically acceptable salt of claim 1 , wherein R is a double bond and one of R ⁵ and R ^6a and R ^6b is absent. 2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 ^X is —OH and R 1 ^Y is unsubstituted C _1-3 alkyl. 16. The compound or pharmaceutically acceptable salt of claim 15, wherein R ^{1 X} is —OH and R 1 ^Y is unsubstituted methyl. 2. The compound or pharmaceutically acceptable salt of claim 1, wherein n is 1 and R ²² is halogen, -CN, -OR ^GA , -N(R ^GA ) ₂ , substituted or unsubstituted C _1-6 alkyl, or substituted or unsubstituted C _3-6 carbocyclyl, where each instance of R ^GA is independently hydrogen, or substituted or unsubstituted C 1-3 _alkyl . 18. The compound or pharmaceutically acceptable salt of claim 17, wherein ^R22 is located at the 4-position of the pyrazolyl. 18. The compound or pharmaceutically acceptable salt of claim 17, wherein ^R22 is located at the 3-position of the pyrazolyl. 18. The compound or pharmaceutically acceptable salt of claim 17, wherein ^R22 is located at the 5-position of the pyrazolyl. ^2. The compound or pharmaceutically acceptable salt of claim 1 , wherein each of R ^<1a> , R ^<1b> , R ^<2a> , R ^<2b> , R ^<4a> , R ^<4b> , R ^<7a> , R ^<7b> , R ^<11a> , R ^<11b> , R<12a>, and R ^<12b> is hydrogen. The compound of formula (I) is a compound of formula (I-a) or (I-b):

or

2. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof. The compound of formula (I-a) is a compound of formula (I-c):

23. The compound of claim 22, which is: or a pharmaceutically acceptable salt thereof. The compound of formula (I-b) is a compound of formula (I-d):

23. The compound of claim 22, which is: or a pharmaceutically acceptable salt thereof. Compound of Formula VIa:

or a pharmaceutically acceptable salt thereof,
During the ceremony,

represents a single or double bond, provided that when a double bond is present, one of R ^6a or R ^6b is absent and R ⁵ is absent;
R ^X is selected from the group consisting of halo, —OH, —OR ^Q1 , and substituted or unsubstituted alkyl, and R ^Q1 is substituted or unsubstituted alkyl;
R ^Y is halo, or substituted or unsubstituted alkyl;
^R3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
^R5 is hydrogen or methyl;
Each instance of R ²² is independently halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —OC(═O)R ^GA , —OC(═O)OR ^GA , —C(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)R ^GA , —OC(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)OR ^GA , —N(R ^GA )C(═O)N(R ^GA ) ₂ , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ OR ^GA , —OS(═O) ₂ R ^GA , —S(═O) ₂ N(R ^GA ) ₂ , —N(R ^GA )S(═O) ₂ R ^GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R ^GA is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two ^RGA groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
Each of R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a and R ^12b is independently hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^A1 , —N(R ^A1 ) ₂ , —SR ^A1 , —C(═O)R ^A1 , —C(═O)OR ^A1 , —C(═O)SR ^A1 , —C(═O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N(R ^A1 ) ₂ , -N(R ^A1 )C(=O)R ^A1 , -N(R ^A1 )C(=NR ^A1 )R ^A1 , -N(R ^A1 )C(=O)OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 )C(=NR ^A1 )N(R ^A1 ) ₂ , -N(R ^A1 )S(=O) ₂ R ^A1 , —N(R ^A1 )S(═O) ₂ OR ^A1 , —N(R ^A1 )S(═O) ₂ N(R ^A1 ) ₂ , —SC(═O)R ^A1 , —SC(═O)OR ^A1 , —SC(═O)SR ^A1 , —SC(═O)N(R ^A1 ) ₂ , —S(═O) ₂ R ^A1 , —S(═O) ₂ OR ^A1 , or —S(═O) ₂ N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, or substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups, together with said intervening atoms, form a substituted or unsubstituted heterocyclic ring;
each of R ^6a and R ^6b is independently selected from the group consisting of hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b are joined to form an oxo (═O) group;
Each of R ^15a , R ^15b , R ^16a and R ^16b is independently hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^C3 , —N(R ^C3 ) ₂ , —SR ^C3 , —C(═O)R ^C3 , —C(═O)OR ^C3 , —C(═O)SR ^C3 , —C(═O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , —OC(═O)OR ^C3 , —OC(═O)N(R ^C3 ) ₂ , —OC(═O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N(R ^C3 ) ₂ , -N(R ^C3 )C(=O)R ^C3 , -N(R ^C3 )C(=NR ^C3 )R ^C3 , -N(R ^C3 )C(=O)OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 )C(=NR ^C3 )N(R ^C3 ) ₂ , -N(R ^C3 )S(=O) ₂ R ^C3 , -N(R ^C3 )S(=O) ₂ OR ^C3 , -N(R ^C3 )S(=O) ₂ N(R ^C3 ) ₂ , —SC(═O)R ^C3 , —SC(═O)OR ^C3 , —SC(═O)SR ^C3 , —SC(═O)N(R ^C3 ) ₂ , —S(═O) _2R ^C3 , —S(═O) _2OR ^C3 , or —S(═O) _2N (R ^C3 ) ₂ , wherein each instance of R ^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; or two R ^{the C3} group together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen or substituted or unsubstituted alkyl;
r is 2,
The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein ^R3 is substituted or unsubstituted _C1-6 alkyl. 27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein ^R3 is _C1-3 alkyl optionally substituted with _C1-3 alkoxy. 28. The compound or pharmaceutically acceptable salt of claim 27, wherein ^R3 is methyl, ethyl, propyl, n-propyl, butyl, -CH ₂ OCH ₃ , or -CH ₂ OCH ₂ CH ₃ . 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R ¹⁹ is hydrogen or unsubstituted C _1-3 alkyl. 30. The compound or pharmaceutically acceptable salt of claim 29, wherein ^R19 is hydrogen or methyl. 26. The compound or pharmaceutically acceptable salt of claim 25, wherein each of R ^15a and R ^15b is independently hydrogen or substituted or unsubstituted alkyl. 32. The compound or pharmaceutically acceptable salt of claim 31, wherein each of R ^15a and R ^15b is independently hydrogen or methyl. 33. The compound or pharmaceutically acceptable salt of claim 32, wherein each of R ^15a and R ^15b is hydrogen. 26. The compound or pharmaceutically acceptable salt of claim 25, wherein each of R ^16a and R ^16b is hydrogen.
26. The compound or pharmaceutically acceptable salt of claim 25, wherein is a single bond and ^R5 is hydrogen or methyl.
36. The compound or pharmaceutically acceptable salt of claim 35, wherein is a single bond and ^R5 is hydrogen.
26. The compound or pharmaceutically acceptable salt of claim 25, wherein is a double bond, and ^R5 and one of ^R6a and ^R6b are absent. 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R 1 ^X is —OH and R 1 ^Y is unsubstituted C _1-3 alkyl. 39. The compound or pharmaceutically acceptable salt of claim 38, wherein R ^{1 X} is —OH and R 1 ^Y is unsubstituted methyl. 26. The compound or pharmaceutically acceptable salt of claim 25, wherein n is 1 and R ²² is halogen, -CN, -OR ^GA , -N(R ^GA ) ₂ , substituted or unsubstituted C _1-6 alkyl, or substituted or unsubstituted C _3-6 carbocyclyl, where each instance of R ^GA is independently hydrogen, or substituted or unsubstituted C _1-3 alkyl. 41. The compound or pharmaceutically acceptable salt of claim 40, wherein ^R22 is located at the 4-position of the pyrazolyl. 41. The compound or pharmaceutically acceptable salt of claim 40, wherein ^R22 is located at the 3-position of the pyrazolyl. 41. The compound or pharmaceutically acceptable salt of claim 40, wherein ^R22 is located at the 5-position of the pyrazolyl. The compound of formula (VIa) is a compound of formula (VIa-a):

26. The compound of claim 25, which is: or a pharmaceutically acceptable salt thereof. The compound of formula (VIa-a) may be a compound of formula (VIa-b):

45. The compound of claim 44, which is: or a pharmaceutically acceptable salt thereof. The compound of formula (VIa-b) is a compound of formula (VIa-c) or (VIa-d):

46. The compound of claim 45, which is: or a pharmaceutically acceptable salt thereof. The compound of formula (VIa) is a compound of formula (VIa-e):

26. The compound of claim 25, which is: or a pharmaceutically acceptable salt thereof. Compound of formula (VIb):

or a pharmaceutically acceptable salt thereof,
During the ceremony,

represents a single or double bond, provided that when a double bond is present, one of R ^6a or R ^6b is absent and R ⁵ is absent;
R ^X is selected from the group consisting of halo, —OH, —OR ^Q1 , and substituted or unsubstituted alkyl, and R ^Q1 is substituted or unsubstituted alkyl;
R ^Y is halo, or substituted or unsubstituted alkyl;
^R3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
^R5 is hydrogen or methyl;
Each instance of R ²² is independently halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —OC(═O)R ^GA , —OC(═O)OR ^GA , —C(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)R ^GA , —OC(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)OR ^GA , —N(R ^GA )C(═O)N(R ^GA ) ₂ , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ OR ^GA , —OS(═O) ₂ R ^GA , —S(═O) ₂ N(R ^GA ) ₂ , —N(R ^GA )S(═O) ₂ R ^GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R ^GA is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two ^RGA groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
Each of R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a and R ^12b is independently hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^A1 , —N(R ^A1 ) ₂ , —SR ^A1 , —C(═O)R ^A1 , —C(═O)OR ^A1 , —C(═O)SR ^A1 , —C(═O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N(R ^A1 ) ₂ , -N(R ^A1 )C(=O)R ^A1 , -N(R ^A1 )C(=NR ^A1 )R ^A1 , -N(R ^A1 )C(=O)OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 )C(=NR ^A1 )N(R ^A1 ) ₂ , -N(R ^A1 )S(=O) ₂ R ^A1 , —N(R ^A1 )S(═O) ₂ OR ^A1 , —N(R ^A1 )S(═O) ₂ N(R ^A1 ) ₂ , —SC(═O)R ^A1 , —SC(═O)OR ^A1 , —SC(═O)SR ^A1 , —SC(═O)N(R ^A1 ) ₂ , —S(═O) ₂ R ^A1 , —S(═O) ₂ OR ^A1 , or —S(═O) ₂ N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, or substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups, together with said intervening atoms, form a substituted or unsubstituted heterocyclic ring;
each of R ^6a and R ^6b is independently selected from the group consisting of hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b are joined to form an oxo (═O) group;
Each of R ^15a , R ^15b , R ^16a and R ^16b is independently hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^C3 , —N(R ^C3 ) ₂ , —SR ^C3 , —C(═O)R ^C3 , —C(═O)OR ^C3 , —C(═O)SR ^C3 , —C(═O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , —OC(═O)OR ^C3 , —OC(═O)N(R ^C3 ) ₂ , —OC(═O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N(R ^C3 ) ₂ , -N(R ^C3 )C(=O)R ^C3 , -N(R ^C3 )C(=NR ^C3 )R ^C3 , -N(R ^C3 )C(=O)OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 )C(=NR ^C3 )N(R ^C3 ) ₂ , -N(R ^C3 )S(=O) ₂ R ^C3 , -N(R ^C3 )S(=O) ₂ OR ^C3 , -N(R ^C3 )S(=O) ₂ N(R ^C3 ) ₂ , —SC(═O)R ^C3 , —SC(═O)OR ^C3 , —SC(═O)SR ^C3 , —SC(═O)N(R ^C3 ) ₂ , —S(═O) _2R ^C3 , —S(═O) _2OR ^C3 , or —S(═O) _2N (R ^C3 ) ₂ , wherein each instance of R ^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; or two R ^{the C3} group together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen or substituted or unsubstituted alkyl;
p is 2,
The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. 49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein ^R3 is substituted or unsubstituted _C1-6 alkyl. 50. The compound of claim 49 or a pharmaceutically acceptable salt thereof, wherein ^R3 is _C1-3 alkyl optionally substituted with _C1-3 alkoxy. 51. The compound or pharmaceutically acceptable salt of claim 50, wherein ^R3 is methyl, ethyl, propyl, n-propyl, butyl, -CH ₂ OCH ₃ , or -CH ₂ OCH ₂ CH ₃ . 49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R ¹⁹ is hydrogen or unsubstituted C _1-3 alkyl. 53. The compound or pharmaceutically acceptable salt of claim 52, wherein R ¹⁹ is hydrogen or methyl. 49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein each of R ^15a and R ^15b is independently hydrogen or substituted or unsubstituted alkyl. 55. The compound or pharmaceutically acceptable salt of claim 54, wherein each of R ^15a and R ^15b is independently hydrogen or methyl. 56. The compound or pharmaceutically acceptable salt of claim 55, wherein each of R ^15a and R ^15b is hydrogen. 49. The compound or pharmaceutically acceptable salt of claim 48, wherein each of R ^16a and R ^16b is hydrogen.
49. The compound or pharmaceutically acceptable salt of claim 48, wherein is a single bond and ^R5 is hydrogen or methyl.
59. The compound or pharmaceutically acceptable salt of claim 58, wherein is a single bond and ^R5 is hydrogen.
49. The compound or pharmaceutically acceptable salt of claim 48, wherein is a double bond and ^R5 and one of ^R6a and ^R6b are absent. 49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R 1 ^X is —OH and R 1 ^Y is unsubstituted C _1-3 alkyl. 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ^{1 X} is —OH and R 1 ^Y is unsubstituted methyl. 49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein n is 1 and R ²² is halogen, -CN, -OR ^GA , -N(R ^GA ) ₂ , substituted or unsubstituted C _1-6 alkyl, or substituted or unsubstituted C _3-6 carbocyclyl, where each instance of R ^GA is independently hydrogen, or substituted or unsubstituted C _1-3 alkyl. 64. The compound or pharmaceutically acceptable salt of claim 63, wherein ^R22 is located at the 4-position of the pyrazolyl. 64. The compound or pharmaceutically acceptable salt of claim 63, wherein ^R22 is located at the 3-position of the pyrazolyl. 64. The compound or pharmaceutically acceptable salt of claim 63, wherein ^R22 is located at the 5-position of the pyrazolyl. The compound of formula (VIb) is a compound of formula (VIb-b):

49. The compound of claim 48, which is: or a pharmaceutically acceptable salt thereof. The compound of formula (VIb-b) is a compound of formula (VIb-c) or (VIb-d):

68. The compound of claim 67, which is: or a pharmaceutically acceptable salt thereof. The compound of formula (VIb) is a compound of formula (VIb-e):

49. The compound of claim 48, which is: or a pharmaceutically acceptable salt thereof. Compound of Formula VII:

or a pharmaceutically acceptable salt thereof,
During the ceremony,

represents a single or double bond, provided that when a double bond is present, one of R ^6a or R ^6b is absent and R ⁵ is absent;
R ^X is selected from the group consisting of halo, —OH, —OR ^Q1 , and substituted or unsubstituted alkyl, and R ^Q1 is substituted or unsubstituted alkyl;
R ^Y is halo, or substituted or unsubstituted alkyl;
^R3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
^R5 is hydrogen or methyl;
Each instance of R ²² is independently halogen, —NO ₂ , —CN, —OR ^GA , —N(R ^GA ) ₂ , —C(═O)R ^GA , —C(═O)OR ^GA , —OC(═O)R ^GA , —OC(═O)OR ^GA , —C(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)R ^GA , —OC(═O)N(R ^GA ) ₂ , —N(R ^GA )C(═O)OR ^GA , —N(R ^GA )C(═O)N(R ^GA ) ₂ , —SR ^GA , —S(═O)R ^GA , —S(═O) ₂ R ^GA , —S(═O) ₂ OR ^GA , —OS(═O) ₂ R ^GA , —S(═O) ₂ N(R ^GA ) ₂ , —N(R ^GA )S(═O) ₂ R ^GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R ^GA is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two ^RGA groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring;
each of R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a and R ^12b independently represents hydrogen, halogen, cyano, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^A1 , —N(R ^A1 ) ₂ , —SR ^A1 , —C(═O)R ^A1 , —C(═O)OR ^A1 , —C(═O)SR ^A1 , —C(═O)N(R ^A1 ) ₂ , —OC(═O)R ^A1 , —OC(═O)OR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -OC(=O)SR ^A1 , -OS(=O) ₂ R ^A1 , -OS(=O) ₂ OR ^A1 , -OS(=O) ₂ N(R ^A1 ) ₂ , -N(R ^A1 )C(=O)R ^A1 , -N(R ^A1 )C(=NR ^A1 )R ^A1 , -N(R ^A1 )C(=O)OR ^A1 , -N(R ^A1 )C(=O)N(R ^A1 ) ₂ , -N(R ^A1 )C(=NR ^A1 )N(R ^A1 ) ₂ , -N(R ^A1 )S(=O) ₂ R ^A1 , -N(R ^A1 )S(=O) ₂ OR ^A1 , —N(R ^A1 )S(=O) ₂ N(R ^A1 ) ₂ , —SC(=O)R ^A1 , —SC(=O)OR ^A1 , —SC(=O)SR ^A1 , —SC(=O)N(R ^A1 ) ₂ , —S(=O) ₂ R ^A1 , —S(=O) ₂ OR ^A1 , or —S(=O) ₂ N(R ^A1 ) ₂ , wherein each instance of R ^A1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C selected from the group consisting of _3-6 carbocyclyl, or substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R ^A1 groups together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
each of R ^6a and R ^6b is independently selected from the group consisting of hydrogen, halogen, cyano, —NO ₂ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R ^6a and R ^6b are joined to form an oxo (═O) group;
Each of R ^15a , R ^15b , R ^16a and R ^16b is independently hydrogen, halogen, —CN, —NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR ^C3 , —N(R ^C3 ) ₂ , —SR ^C3 , —C(═O)R ^C3 , —C(═O)OR ^C3 , —C(═O)SR ^C3 , —C(═O)N(R ^C3 ) ₂ , —OC(═O)R ^C3 , —OC(═O)OR ^C3 , —OC(═O)N(R ^C3 ) ₂ , —OC(═O)SR ^C3 , -OS(=O) ₂ R ^C3 , -OS(=O) ₂ OR ^C3 , -OS(=O) ₂ N(R ^C3 ) ₂ , -N(R ^C3 )C(=O)R ^C3 , -N(R ^C3 )C(=NR ^C3 )R ^C3 , -N(R ^C3 )C(=O)OR ^C3 , -N(R ^C3 )C(=O)N(R ^C3 ) ₂ , -N(R ^C3 )C(=NR ^C3 )N(R ^C3 ) ₂ , -N(R ^C3 )S(=O) ₂ R ^C3 , -N(R ^C3 )S(=O) ₂ OR ^C3 , -N(R ^C3 )S(=O) ₂ N(R ^C3 ) ₂ , —SC(═O)R ^C3 , —SC(═O)OR ^C3 , —SC(═O)SR ^C3 , —SC(═O)N(R ^C3 ) ₂ , —S(═O) _2R ^C3 , —S(═O) _2OR ^C3 , or —S(═O) _2N (R ^C3 ) ₂ , wherein each instance of R ^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; or two R ^{the C3} group together with said intervening atoms form a substituted or unsubstituted heterocyclic ring;
R ¹⁹ is hydrogen or substituted or unsubstituted alkyl;
The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. 71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein ^R3 is substituted or unsubstituted _C1-6 alkyl. 72. The compound of claim 71, or a pharmaceutically acceptable salt thereof, wherein ^R3 is _C1-3 alkyl optionally substituted with _C1-3 alkoxy. 73. The compound of claim 72 or a pharmaceutically acceptable salt thereof, wherein ^R3 is methyl, ethyl, propyl, n-propyl, butyl, -CH ₂ OCH ₃ , or -CH ₂ OCH ₂ CH ₃ . 71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein R ¹⁹ is hydrogen or unsubstituted C _1-3 alkyl. 75. The compound or pharmaceutically acceptable salt of claim 74, wherein R ¹⁹ is hydrogen or methyl. 71. The compound or pharmaceutically acceptable salt of claim 70, wherein each of R ^15a and R ^15b is independently hydrogen, or substituted or unsubstituted alkyl. 77. The compound or pharmaceutically acceptable salt of claim 76, wherein each of R ^15a and R ^15b is independently hydrogen or methyl. 78. The compound or pharmaceutically acceptable salt of claim 77, wherein each of R ^15a and R ^15b is hydrogen. 71. The compound or pharmaceutically acceptable salt of claim 70, wherein each of R ^16a and R ^16b is hydrogen.
71. The compound or pharmaceutically acceptable salt of claim 70, wherein is a single bond and ^R5 is hydrogen or methyl.
81. The compound or pharmaceutically acceptable salt of claim 80, wherein R is a single bond and R ⁵ is hydrogen.
71. The compound or pharmaceutically acceptable salt of claim 70, wherein is a double bond, and ^R5 and one of ^R6a and ^R6b are absent. 71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein R 1 ^X is —OH and R 1 ^Y is unsubstituted C _1-3 alkyl. 84. The compound of claim 83, or a pharmaceutically acceptable salt thereof, wherein R ^{1 X} is —OH and R 1 ^Y is unsubstituted methyl. 71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein n is 1 and R ²² is halogen, -CN, -OR ^GA , -N(R ^GA ) ₂ , substituted or unsubstituted C _1-6 alkyl, or substituted or unsubstituted C _3-6 carbocyclyl, where each instance of R ^GA is independently hydrogen, or substituted or unsubstituted C _1-3 alkyl. 86. The compound or pharmaceutically acceptable salt of claim 85, wherein ^R22 is located at the 4-position of the pyrazolyl. 86. The compound or pharmaceutically acceptable salt of claim 85, wherein ^R22 is located at the 3-position of the pyrazolyl. 86. The compound or pharmaceutically acceptable salt of claim 85, wherein ^R22 is located at the 5-position of the pyrazolyl. The compound of formula (VII) is a compound of formula (VII-a):

or a pharmaceutically acceptable salt thereof. The compound of formula (VII) is a compound of formula (VII-b):

or a pharmaceutically acceptable salt thereof. The compound of formula (VII-b) is a compound of formula (VII-c):

91. The compound of claim 90, which is: or a pharmaceutically acceptable salt thereof. The compound is



A compound selected from the group consisting of: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: Structural formula

93. The compound of claim 92, having the formula: A pharmaceutically acceptable salt of the compound of any one of claims 92 to 121. A pharmaceutical composition comprising a compound according to any one of claims 1 to 121 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. R ²² Each instance of is independently a halogen, —NO ₂ , -CN, -OR ^G.A. , -N(R ^G.A. ) ₂ , -C(=O)R ^G.A. , -C(=O)OR ^G.A. , -OC(=O)R ^G.A. , -OC(=O)OR ^G.A. , -C(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O)R ^G.A. , -OC(=O)N(R ^G.A. ) ₂ , -N(R ^G.A. ) C(=O) OR ^G.A. , -N(R ^G.A. )C(=O)N(R ^G.A. ) ₂ , -SR ^G.A. , -S(=O)R ^G.A. , -S(=O) ₂ R ^G.A. , -S(=O) ₂ OR ^G.A. , -OS(=O) ₂ R ^G.A. , -S(=O) ₂ N (R ^G.A. ) ₂ , -N(R ^G.A. ) S(=O) ₂ R ^G.A. , unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, and unsubstituted heteroaryl; R ^G.A. Each example of _{1 to 6} Alkyl, unsubstituted C _{2 to 6} Alkenyl, unsubstituted C _{2 to 6} Alkynyl, unsubstituted C _{3 to 6} 71. The compound or pharmaceutically acceptable salt of any one of claims 25, 48, or 70, which is carbocyclyl, unsubstituted 3- to 6-membered heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl.